Sulfonamide compounds as protease inhibitors

ABSTRACT

The present invention relates to novel cysteine protease inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making.

CROSS-REFERENCE

[0001] This application claims priority under 35 USC 119(e) to U.S. Provisional application Serial No. 60/322,220, filed on Sep. 14, 2001, the disclosure of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsins B, K, L or S.

[0004] 2. State of the Art

[0005] Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g., as a result of increased expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, increased cathepsin B levels and redistribution of the enzyme are found in tumors; thus, suggesting a role for the enzyme in tumor invasion and metastasis. In addition, aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.

[0006] The prominent expression of cathepsin K in osteoclasts and osteoclast-related multinucleated cells and its high collagenolytic activity suggest that the enzyme is involved in ososteoclast-mediated bone resorption and, hence, in bone abnormalities such as occurs in osteoporosis. In addition, cathepsin K expression in the lung and its elastinolytic activity suggest that the enzyme plays a role in pulmonary disorders as well.

[0007] Cathepsin L is implicated in normal lysosomal proteolysis as well as several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer's disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis. In addition, cathepsin S is implicated in: allergic disorders, including, but not limited to asthma; and allogeneic immune reponses, including, but not limited to, rejection of organ transplants or tissue grafts.

[0008] In view of the number of diseases wherein it is recognized that an increase in cysteine protease activity contributes to the pathology and/or symptomatology of the disease, molecules which are shown to inhibit the activity of this class of enzymes, in particular molecules which are inhibitors of cathepsins B, K, L and/or S, will be useful as therapeutic agents.

SUMMARY OF THE INVENTION

[0009] In one aspect, this invention is directed to a compound of Formula I:

[0010] in which:

[0011] R¹ and R² independently are —R⁸, —X²OR⁸, —X²SR⁸, —X²S(O)R₈, —X²S(O)₂R⁸, —X²C(O)R⁸, —X²C(OR⁷)R⁷R⁸, —X²C(O)OR⁸, —X²NR⁷R⁸, —X²NR⁷C(O)OR⁸, —X²C(O)NR⁷R⁸, —X²S(O)₂NR⁷R⁸, —X²NR⁷C(O)NR⁷R⁸ or —X²NR⁷C(NR⁷)NR⁷R⁸, wherein X² is (C₁₋₆)alkylene, R⁷ is hydrogen or (C₁₋₆)alkyl; R⁸ is hydrogen, (C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicyclo-aryl(C₀₋₃)alkyl; wherein within R⁸ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with halo, —R⁹, —X³OR⁹, —X³SR⁹, —X³S(O)R⁹, —X³S(O)₂R⁹, —X³C(O)R⁹, —X³C(OR⁹)R⁹, —X³C(O)OR⁹, —X³NR⁹R¹⁰, —X³NR⁹C(O)OR⁹, —X³C(O)NR⁹R¹⁰, —X³S(O)₂NR⁹R¹⁰, —X³NR⁹C(O)NR⁹R¹⁰ or —X³NR⁹C(NR⁹)NR⁹R¹⁰; wherein X³ is a bond or (C₁₋₆)alkylene, R⁹ is hydrogen or (C₁₋₆)alkyl and R¹⁰ is cycloalkyl;

[0012] R³ is —R¹¹, —X³OR¹¹, —X³SR¹¹, —X³S(O)R¹¹, —X³S(O)₂R¹¹, —X³C(O)R¹¹, —X³C(O)OR¹¹, —X³NR¹¹, R¹², —X³NR¹²C(O)OR¹¹, —X³C(O)NR¹¹R¹², —X³S(O)₂NR¹¹R¹², —X³NR¹²C(O)NR¹¹R¹² or —X³NR¹²C(NR¹²)NR¹¹R¹², wherein X³ is as described above, R¹¹ is hydrogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl-(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloary(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl and R¹² is hydrogen or (C₁₋₆)alkyl, wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R³ are optionally independently substituted with halo, nitro, cyano, (C₁₋₆)alkyl, halo-substituted(C₁₋₆)alkyl, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —C(O)NR⁷R⁷, —S(O)₂NR⁷R⁷, —X²NR⁷R⁷, —X²NR⁷C(O)OR⁷, —X²NR⁷C(O)NR⁷R⁷ or —X²NR⁷C(NR⁷NR⁷R⁷, wherein X² and R⁷ are as defined above;

[0013] R⁴ is hydrogen or (C₁₋₆)alkyl;

[0014] R⁵ is (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, or —X²S(O)R¹⁴ where X² is as defined above and R¹⁴ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl; or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form (C₃₋₇)cycloalkylene;

[0015] R⁶ is hydrogen or —X⁴X⁵R¹³, wherein X⁴ is —C(O)—, X⁵ is a bond, —O— or —NR¹²—, wherein R¹² is as defined above, and R¹³ is (C₁₋₆)alkyl, —R¹⁴, —X³OR¹⁴, —X³SR¹⁴, —X³S(O)R¹⁴, —X³S(O)₂R¹⁴, —X³C(O)R¹⁴, —X³C(O)OR¹⁴, —X³NR¹⁴R¹⁵, —X³NR¹⁵C(O)OR¹⁴, —X³C(O)NR¹⁴R¹⁵, —X³S(O)₂NR¹⁴R¹⁵, —X³NR¹⁵C(O)NR¹⁴R¹⁵ or —X³NR¹⁵C(NR¹⁵)NR¹⁴R¹⁵, wherein X³ is as defined above; R¹⁴ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl; R¹⁵ is hydrogen or (C₁₋₆)alkyl; and within R¹⁴ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —OCF₃, —CF₃, —OH, halo, —R¹⁶, —X³OR¹⁶, —X³OR¹⁵, —X³C(O)R¹⁵, —X³SR¹⁶, —X³S(O)R¹⁶, —R¹⁵, —X³S(O)₂R¹⁶, —X³C(O)R¹⁶, —X³C(O)OR¹⁵, —X³NR¹⁵R¹⁵, —X³NR¹⁵C(O)OR¹⁵, —X³C(O)NR¹⁵R¹⁶, —X³S(O)₂NR¹⁵R¹⁶, —X³NR¹⁵C(O)NR¹⁵R¹⁵ or —X³NR¹⁵C(NR¹⁵)NR¹⁵R¹⁶, wherein X³ and R¹⁵ are as defined above and R¹⁶ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl-(C₀₋₃)alkyl and within R¹⁶ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —R¹⁵, —R¹⁷, —X³OR¹⁷, —X³SR¹⁷, —X³S(O)R¹⁷, —X³S(O)₂R¹⁷, —X³C(O)R¹⁷, —X³C(O)OR¹⁷, —X³NR¹⁵R¹⁷, —X³NR¹⁵R¹⁵, —X³NR¹⁵C(O)OR¹⁷, —X³C(O)NR¹⁵R¹⁷, —X³S(O)₂NR¹⁵R¹⁷, —X³NR¹⁵C(O)NR¹⁵R¹⁷ or —X³NR¹⁵C(NR¹⁵)NR¹⁵R¹⁷, wherein X³ and R¹⁵ are as defined above and R¹⁷ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloary(C₀₋₃)alkyl and within R¹⁷ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —R¹⁸, —X³OR¹⁸, —X³SR¹⁸, —X³S(O)R¹⁸, —X³S(O)₂R¹⁸, —X³C(O)R¹⁸, —X³C(O)OR¹⁸, —X³NR¹⁵R¹⁸, —X³NR¹⁵C(O)OR¹⁸, —X³C(O)NR¹⁵R¹⁸, —X³S(O)₂NR¹⁵R¹⁸, —X³NR¹⁵C(O)NR¹⁵R¹⁸ or —X³NR¹⁵C(NR¹⁵)NR¹⁵R¹⁸, wherein X³ and R¹⁵ are as defined above and R¹⁸ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl; with the proviso that only one (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl is present within R⁶, or

[0016] a pharmaceutically acceptable salt thereof.

[0017] A second aspect of this invention is a pharmaceutical composition that contains a compound of Formula I or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.

[0018] A third aspect of this invention is a method of treating a disease in an animal in which inhibition of a cysteine protease can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease. Said method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt thereof.

[0019] A fourth aspect of this invention is the processes for preparing compounds of Formula I and the pharmaceutically acceptable salts thereof as set forth in “Detailed Description of the Invention”.

DETAILED DESCRIPTION OF THE INVENTION

[0020] Definitions:

[0021] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the meanings given this Section:

[0022] “Aliphatic” means a moiety characterized by straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.

[0023] “Alkyl” represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having the number of carbon atoms indicated (e.g., (C₁₋₆)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g., as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when zero atoms are indicated means a bond (e.g., (C₆₋₁₂)aryl(C₀₋₃)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, and the like).

[0024] “Alkylene”, unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g., (C₂₋₅)alkylene includes ethylene (—CH₂CH₂— or —CH(CH₃)—), 1-methylethylene (—CH(CH₃)CH₂—), trimethylene (—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—), pentamethylene (—CH₂CH₂CH₂CH₂CH₂—), and the like.

[0025] “Alkyloxy” means the radical —OR, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C₁₋₆)alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, and the like).

[0026] “Amino” means the radical —NH₂. Unless indicated otherwise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

[0027] “Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).

[0028] “Aromatic” means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring are sp² hybridized and the total number of pi electrons is equal to 4n+2.

[0029] “Aryl” means a monocyclic or bicyclic ring assembly (fused or linked by a single bond) containing the total number of ring carbon atoms indicated, wherein each ring is aromatic or when fused with another ring forms an aromatic ring assembly. For example, (C₆₋₁₂)aryl includes phenyl, naphthalenyl, and biphenylyl.

[0030] “Bicycloaryl” means a bicyclic ring assembly containing the number of annular carbon atoms indicated, wherein the rings are linked by a single bond or fused and one, but not both, of the rings comprising the assembly is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, (C₉₋₁₂)bicycloaryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl, 2,4-dioxo-1,2,3,4-tetrahydro-naphthalenyl, or the like.

[0031] “Carbamoyl” means the radical —C(O)NH₂. Unless indicated otherwise, the compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.

[0032] “Cycloalkyl” means a saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of annular carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, (C₃₋₁₂)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthalenyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo-[2.2.1]hept-1-yl, and the like.

[0033] “Cycloalkylene” means a divalent saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of annular carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, (C₃₋₁₂)cycloalkylene includes cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexenylene, 2,5-cyclohexadienylene, bicyclohexylylene, and the like.

[0034] “Disease” specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the “side effects” of such therapy.

[0035] “Halo” means fluoro, chloro, bromo or iodo.

[0036] “Haloalkyl” or “halo-substituted alkyl” means an alkyl group as defined above that is substituted with a halo group as defined above e.g., trifluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, and the like.

[0037] “Heteroaryl” means aryl, as defined herein, provided that one or more, preferably one to four, of the ring carbon atoms indicated, are replaced by a heteroatom moiety selected from —N═, —N^(+(O) ⁻)═, —NR—, —O— or —S—, wherein R is hydrogen, (C₁₋₆)alkyl or a protecting group, and each ring contained therein is comprised of 5 to 6 annular members (e.g., hetero(C₅₋₁₄)aryl includes thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, benzo[b]thienyl, isobenzofuranyl, purinyl, isoquinolyl, pterdinyl, perimidinyl, imidazolyl, 1-methylimidazolyl, 1-benzylimidazolyl, pyridyl, pyrazolyl, pyrazinyl, tetrazolyl, quinolyl, [2,4′]bipyridinylyl, 2-phenylpyridyl, 4-thiazol-4-ylphenyl, 1H-imidazol-1-ylphenyl, and the like). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.

[0038] “Heterobicycloaryl” means bicycloaryl, as defined herein, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety selected from —N—, —NR—, —O— or —S—, wherein R is hydrogen, (C₁₋₆)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, hetero(C₈₋₁₂)bicycloaryl includes 3,4-dihydro-2H-quinolinyl, 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H-[1,8]naphthyridinyl, morpholinylpyridyl, piperidinylphenyl, 1,2,3,4,5,6-hexahydro-[2,2′]bipyridinylyl, 2,4-dioxo-3,4-dihydro-2H-quinazolinyl, 3-oxo-2,3-dihydrobenzo-[1,4]oxazinyl, and the like.

[0039] “Heterocycloalkyl” means cycloalkyl, as defined herein, provided that one or more, preferably one to three, of the annular carbon atoms indicated is replaced by heteroatom moiety selected from —N—, —NR—, —O— or —S—, wherein R is hydrogen, (C₁₋₆)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term hetero(C₃₋₁₄)cycloalkyl includes piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, [1,4′]bipiperidinylyl, 1′,2′-dihydro-2H-[1,4′]bipyridinylyl, 1-morpholin-4-ylpiperidinyl, and the like). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like. For example, a compound of Formula I wherein R¹ is piperidin-4-ylcarbonyl may exist as either the unprotected or a protected derivative, e.g., wherein R¹ is 1-tert-butoxycarbonylpiperidin-4-ylcarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.

[0040] “Hydroxy” means the radical —OH. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like and both the unprotected and protected derivatives fall within the scope of the invention.

[0041] “Iminoketone derivative” means a derivative containing the moiety —C(NR)—, wherein R is hydrogen or (C₁₋₆)alkyl.

[0042] “Isomers” mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “steroisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes “optical isomers”. A carbon atom bonded to four nonidentical substituents is termed a “chiral center”. A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a “racemic mixture”. A compound that has more than one chiral center has 2^(n−1) enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diasteromer or as a mixture of diastereomers, termed a “diastereomeric mixture”. When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see “Advanced Organic Chemistry”, 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to encompass all possible stereoisomers and any mixture, racemic or otherwise, thereof.

[0043] “Ketone derivative” means a derivative containing the moiety —C(O)—.

[0044] “Leaving group” has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions, and includes, halogen, hydroxy, alkyloxy, alkylsulfonyloxy (e.g., mesyloxy, ethanesulfonyloxy, or the like), arylsulfonyloxy (e.g., benzenesulfonyloxy and tosyloxy, thienyloxy), dihalophosphinoyloxy, tetrahalophosphaoxy, and the like.

[0045] “Nitro” means the radical —NO₂.

[0046] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase “any 1 to 3 annular atoms of any aromatic ring with available valences comprising R⁶ optionally independently is substituted” means that the aromatic ring referred to may or may not be substituted in order to fall within the scope of the invention.

[0047] “N-oxide derivatives” means derivatives of compounds of Formula I in which nitrogen atom(s) is in an oxidized state (i.e., N→O) and which possess the desired pharmacological activity. The n-oxide derivative of a compound of Formula I is within the scope of this invention.

[0048] “Oxo” means the radical=O.

[0049] “Pathology” of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.

[0050] “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.

[0051] “Pharmaceutically acceptable salts” means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.

[0052] Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

[0053] “Prodrug derivatives” means derivatives of compounds of Formula I which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I. All prodrugs of a compound of Formula I are within the scope of this invention.

[0054] “Protected derivatives” means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protective groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active cysteine protease inhibitors. A comprehensive list of suitable protective groups can be found in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (3rd Edition) 1999. All protective derivatives of a compound of Formula I are within the scope of this invention.

[0055] “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.

[0056] “Thioketone derivative” means a derivative containing the moiety —C(S)—.

[0057] “Treatment” or “treating” means any administration of a compound of the present invention and includes:

[0058] preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,

[0059] inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or

[0060] ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).

[0061] Abbreviations used: acetonitrile (ACN); t-butyloxycarbonyl (BOC); dichloromethane (DCM); 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); diisopropylcarbodiimide (DIC); 4-dimethylamino-pyridine (DMAP); electrospray ionization (ESI); diethyl ether (Et₂O); High performance liquid chromatography (HPLC); Liquid Chromatography/Mass Spectroscopy (LC/MS); tetrahydrofuran (THF); trifluoroacetic acid (TFA); tetrapyrrolidinophosphonium hexafluorophosphate (PyBOP); N-{(dimethylamino)(1H-1,2,3-triazole[4,5-b]pyridin-1-yl)-methylene}-N-methylmethan-aminium hexafluorophosphate N-oxide (HATU); 4-dimethylamino-pyridine (DMAP); dicyclohexylcarbodiimide (DCC); dimethylformamide (DMF).

[0062] Nomenclature:

[0063] The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc. Alternatively, the compounds are named by AutoNom 2.1 or 4.0 (Beilstein Information System, Inc.). For example, compounds of Formula I in which:

[0064] R¹ is 4-methoxy-benzyl; R² is 4-phenylethyl; R³ is cyclohexylmethyl; and R⁴ is acetyl is named 2-acetylamino-3-cyclohexyl-N-[2-(4-methoxy-phenylsulfomoyl)-ethyl]-propionamide;

[0065] R¹ is 4-methoxy-benzyl; R² is 4-phenylethyl; R³ is isobutyl; and R⁴ is pyridine-3-carbonyl is named N-(1-{1-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-nicotinamide.

[0066] Presently Preferred Embodiments:

[0067] While the broadest definition of this invention is set forth in the Summary of the Invention, certain aspects of the invention are preferred. Preferred aspects of the invention are

[0068] R¹ is —R⁸, —X²OR⁸, —X²C(O)R⁸, —X²C(OR⁷)R⁷R⁸, —X²NR⁷R⁸ or —X²NR⁷C(O)OR⁸; wherein X² is (C₁₋₆)alkylene; R⁷ is hydrogen or (C₁₋₆)alkyl; R⁸ is hydrogen, (C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl or hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl; wherein within R⁸ said cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted with halo, —R⁹, —X³OR⁹, —X³C(O)R⁹, —X³C(OR⁹)R⁹, —X³NR⁹R¹⁰ or —X³NR⁹C(O)OR⁹; wherein X³ is a bond or (C₁₋₆)alkylene, R⁹ is hydrogen or (C₁₋₆)alkyl and R¹⁰ is cycloalkyl;

[0069] R² is hydrogen;

[0070] R³ is —R¹¹, —X³NR¹¹R¹² or —X³NR¹²C(O)OR¹¹; wherein X³ is a bond or (C₁₋₆)alkylene, R¹¹ is hydrogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl and R¹² is hydrogen or (C₁₋₆)alkyl, wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R³ are optionally independently substituted with halo, nitro, cyano, (C₁₋₆)alkyl, halo-substituted(C₁₋₆)alkyl, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —C(O)NR⁷R⁷, —S(O)₂NR⁷R⁷, —X²NR⁷R⁷, —X²NR⁷C(O)OR⁷, —X²NR⁷C(O)NR⁷R⁷ or —X²NR⁷C(NR⁷NR⁷R⁷, wherein X² and R⁷are as defined above;

[0071] R⁴ is hydrogen or (C₁₋₆)alkyl;

[0072] R⁵ is (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, or —X²S(O)R¹⁴ where X² is as defined above and R¹⁴ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl; preferably, R⁵ is (C₁₋₆)alkyl or (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl; or

[0073] R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form (C₃₋₇)cycloalkylene;

[0074] R⁶ is hydrogen or —X⁴X⁵R¹³, wherein X⁴ is —C(O)—, X⁵ is a bond, —O— or —NR¹²—, wherein R¹² is as defined above, and R¹³ is (C₁₋₆)alkyl or —R¹⁴ wherein R¹⁴ is (C₃₋₁₂)cycloalkyl(C₀₋₃)-alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl)C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl; and within R¹⁴ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —OCF₃, —CF₃, —OH, halo, —R¹⁶, —X³OR¹⁶, —X³OR¹⁵, —X³C(O)R¹⁵, —R¹⁵, —X³C(O)R¹⁶, —X³C(O)OR¹⁵, —X³NR¹⁵R¹⁵, —X³NR¹⁵C(O)OR¹⁵, wherein X³ is as defined above, R¹⁵ is hydrogen or (C₁₋₆)alkyl; and R¹⁶ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl-(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl or hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, and within R¹⁶ said cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted with —R¹⁵, —R¹⁷, —X³NR¹⁵R¹⁷, —X³NR¹⁵R¹⁵ wherein X³ and R¹⁵ are as defined above and R¹⁷ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl or hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl; with the proviso that only one (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl is present within R⁶; and the pharmaceutically acceptable salts thereof.

[0075] More preferably, R¹ is 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-chlorophenyl, 3-chloro-phenyl, 2-chlorophenyl, 4-hydroxyphenyl, 2-acetylphenyl, 2-(1-hydroxyethyl)phenyl, 2-phenylaminoethyl, pyridin-4-ylphenyl, pyridin-3-ylphenyl, pyridin-2-ylphenyl, 1H-imidazol-2-yl, piperidin-4-yl or 1-methylpiperidin-4-yl;

[0076] R² is hydrogen;

[0077] R³ is hydrogen, phenethyl, 4-aminobutyl, butyl or 4-benzyloxycarbonylaminobutyl;

[0078] R⁴ is hydrogen;

[0079] R⁵ is isobutyl, sec-butyl or cyclohexylmethyl; or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form cyclohexyl; and

[0080] R⁶ is selected from the group consisting of benzoyl, morpholin-4-ylcarbonyl, acetyl, furan-3-ylcarbonyl, 2-methoxybenzoyl, 3-methoxybenzoyl, naphthalen-2-ylcarbonyl, benzo[1,3]dioxol-5-ylcarbonyl, 3-pyridin-3-ylacryloyl, benzofuran-2-ylcarbonyl, furan-2-ylcarbonyl, tert-butoxycarbonyl, biphenyl-4-carbonyl, quinolin-2-ylcarbonyl, quinolin-3-ylcarbonyl, 3-acetylbenzoyl, 4-phenoxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, pyridin-3-ylcarbonyl, 3-(tert-butoxycarbonylaminomethyl)benzoyl, 4-carbonylpiperazin-1-ylcarboxylic acid tert-butyl ester, 4-carbonylpiperazin-1-ylcarboxylic acid ethyl ester, 4-(furan-2-ylcarbonyl)piperazin-1-ylcarbonyl, pyridin-4-ylcarbonyl, 1-oxypyridin-4-ylcarbonyl, 1-oxypyridin-3-ylcarbonyl, thiophen-2-ylcarbonyl, thiophen-3-ylcarbonyl, 4-benzoylbenzoyl, 5-methylthiophen-2-ylcarbonyl, 3-chlorothiophen-2-ylcarbonyl, 3-bromothiophen-2-ylcarbonyl, 4-chlorobenzoyl, 3-flouro-4-methoxybenzoyl, 4-methoxy-benzoyl, 4-triflouromethoxybenzoyl, 3,4-diflourobenzoyl, 4-fluorobenzoyl, 3,4-dimethoxy-benzoyl, 3-methylbenzoyl, 4-bromobenzoyl, 4-triflouromethylbenzoyl, 3-benzoylbenzoyl, cyclopentanecarbonyl, benzo[b]thiophen-2-ylcarbonyl, 3-chlorobenzo[b]thiophen-2-ylcarbonyl, formamylmethyl ester, 4-methylpentanoyl, formamylisobutyl ester, formamylmonoallyl ester, formamylisopropyl ester, N,N-dimethylformamyl, N-isopropylformamyl, N-pyridin-4-yl-formamyl, N-pyridin-3-ylformamyl, 3-phenylacryloyl, 1H-indol-5-ylcarbonyl, pyridin-2-ylcarbonyl, pyrazin-2-ylcarbonyl, 3-hydroxypyridin-2-ylcarbonyl, 2-aminopyridin-3-ylcarbonyl, 2-hydroxypyridin-3-ylcarbonyl, 6-aminopyridin-3-ylcarbonyl, 6-hydroxypyridin-3-ylcarbonyl, pyridazin-4-ylcarbonyl, 3-phenoxybenzoyl, 1-oxo-1,3-dihydroisoindol-2-ylcarbonyl, 4-(4-methylpiperazin-1-yl)benzoyl, 4-morpholin-4-ylbenzoyl, 4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzoyl, 3-aminobenzoyl, 4-methylpiperazin-1-ylcarbonyl and benzylacetyl.

[0081] More preferably, R¹ is 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-chlorophenyl, 3-chloro-phenyl, 2-chlorophenyl, 4-hydroxyphenyl, 2-acetylphenyl, 2-(1-hydroxyethyl)phenyl, 2-phenylaminoethyl, pyridin-4-ylphenyl, pyridin-3-ylphenyl, pyridin-2-ylphenyl, 1H-imidazol-2-yl, piperidin-4-yl or 1-methylpiperidin-4-yl;

[0082] R² is hydrogen;

[0083] R³ is benzylsulfonylmethyl;

[0084] R⁴ is hydrogen;

[0085] R⁵ is isobutyl, sec-butyl or cyclohexylmethyl; or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form cyclohexyl; and

[0086] R⁶ is selected from the group consisting of R⁶ is selected from the group consisting of benzoyl, morpholin-4-ylcarbonyl, acetyl, furan-3-ylcarbonyl, 2-methoxybenzoyl, 3-methoxybenzoyl, naphthalen-2-ylcarbonyl, benzo[1,3]dioxol-5-ylcarbonyl, 3-pyridin-3-ylacryloyl, benzofuran-2-ylcarbonyl, furan-2-ylcarbonyl, tert-butoxycarbonyl, biphenyl-4-carbonyl, quinolin-2-ylcarbonyl, quinolin-3-ylcarbonyl, 3-acetylbenzoyl, 4-phenoxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, pyridin-3-ylcarbonyl, 3-(tert-butoxycarbonylaminomethyl)benzoyl, 4-carbonylpiperazin-1-ylcarboxylic acid tert-butyl ester, 4-carbonylpiperazin-1-ylcarboxylic acid ethyl ester, 4-(furan-2-ylcarbonyl)piperazin-1-ylcarbonyl, pyridin-4-ylcarbonyl, 1-oxypyridin-4-ylcarbonyl, 1-oxypyridin-3-ylcarbonyl, thiophen-2-ylcarbonyl, thiophen-3-ylcarbonyl, 4-benzoylbenzoyl, 5-methylthiophen-2-ylcarbonyl, 3-chlorothiophen-2-ylcarbonyl, 3-bromothiophen-2-ylcarbonyl, 4-chlorobenzoyl, 3-flouro-4-methoxybenzoyl, 4-methoxy-benzoyl, 4-triflouromethoxybenzoyl, 3,4-diflourobenzoyl, 4-fluorobenzoyl, 3,4-dimethoxy-benzoyl, 3-methylbenzoyl, 4-bromobenzoyl, 4-triflouromethylbenzoyl, 3-benzoylbenzoyl, cyclopentanecarbonyl, benzo[b]thiophen-2-ylcarbonyl, 3-chlorobenzo[b]thiophen-2-ylcarbonyl, formamylmethyl ester, 4-methylpentanoyl, formamylisobutyl ester, formamylmonoallyl ester, formamylisopropyl ester, N,N-dimethylformamyl, N-isopropylformamyl, N-pyridin-4-yl-formamyl, N-pyridin-3-ylformamyl, 3-phenylacryloyl, 1H-indol-5-ylcarbonyl, pyridin-2-ylcarbonyl, pyrazin-2-ylcarbonyl, 3-hydroxypyridin-2-ylcarbonyl, 2-aminopyridin-3-ylcarbonyl, 2-hydroxypyridin-3-ylcarbonyl, 6-aminopyridin-3-ylcarbonyl, 6-hydroxypyridin-3-ylcarbonyl, pyridazin-4-ylcarbonyl, 3-phenoxybenzoyl, 1-oxo-1,3-dihydroisoindol-2-ylcarbonyl, 4-(4-methylpiperazin-1-yl)benzoyl, 4-morpholin-4-ylbenzoyl, 4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzoyl, 4-(2-dimethylaminothiazol-4-yl)benzoyl, quinolin-6-ylcarbonyl, 4-dimethylamino-benzoyl, 3-aminobenzoyl, 4-methylpiperazin-1-ylcarbonyl and benzylacetyl.

[0087] Even more preferably, R¹ is 4-methoxyphenyl, 3-acetylphenyl, 3-(1-hydroxyethyl)-phenyl, 2-(phenylamino)ethyl or 4-hydroxyphenyl;

[0088] R² is hydrogen;

[0089] R³ is hydrogen, 2-phenethyl, 4-aminobutyl, or 4-benzyloxycarbonylaminobutyl;

[0090] R⁴ is hydrogen;

[0091] R⁵ is isobutyl, sec-butyl or cyclohexylmethyl; or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form cyclohexyl; and

[0092] R⁶ is selected from the group consisting of acetyl, pyridin-3-ylcarbonyl, 3-(tert-butoxycarbonylamino)benzoyl, pyridin-4-ylcarbonyl, 1H-indol-5-ylcarbonyl, benzyloxycarbonyl, 3-aminobenzoyl, 4-methylpiperazin-1-ylcarbonyl, quinolin-6-ylcarbonyl, 4-[2-(pyridin-3-ylamino)thiazol-4-yl]benzoyl, 4-dimethylaminobenzoyl, morpholin-4-yl-carbonyl, 4-(2-dimethylaminothiazol-4-yl)benzoyl, tert-butoxycarbonyl, 4-(4-ethylpiperazin-1-yl)-benzoyl, and 4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzoyl.

[0093] A number of different preferences have been given above, and following any one of these preferences results in a compound of this invention that is more presently preferred than a compound in which that particular preference is not followed. However, these preferences are generally independent [although some (alternative) preferences are mutually exclusive], and additive; and following more than one of these preferences may result in a more presently preferred compound than one in which fewer of the preferences are followed.

[0094] Particular compounds of the invention are selected from the compounds formed by joining C* of one of the fragments (A1 to A77) shown in Table 1 to the nitrogen atom (*N) of one of the fragments (B1 to B4) shown in Table 2, and joining the methine carbon atom (CH*) of one of the fragments (B1 to B4) shown in Table 2 to the acyl carbon atom (C*) of one of the fragments (C1 to C3 1) depicted in Table 3. TABLE 1 A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

A42

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

A56

A57

A58

A59

A60

A61

A62

A63

A64

A65

A66

A67

A68

A69

A70

A71

A72

A73

A74

A75

A76

A77

[0095] TABLE 2 B1

B2

B3

B4

[0096] TABLE 3 C1

C2

C3

C4

C5

C6

C7

C8

C9

C10

C11

C12

C13

C14

C15

C16

C17

C18

C19

C20

C21

C22

C23

C24

C25

C26

C27

C28

C29

C30

C31

[0097] Particularly preferred compounds of “A”, “B”, and “C” combinations are illustrated in table 4, infra: TABLE 4 A1-B1-C1 A12-B1-C1  A23-B1-C1  A34-B1-C1  A2-B1-C1 A13-B1-C1  A24-B1-C1  A35-B1-C1  A3-B1-C1 A14-B1-C1  A25-B1-C1  A36-B1-C1  A4-B1-C1 A15-B1-C1  A26-B1-C1  A37-B1-C1  A5-B1-C1 A16-B1-C1  A27-B1-C1  A38-B1-C1  A6-B1-C1 A17-B1-C1  A28-B1-C1  A39-B1-C1  A7-B1-C1 A18-B1-C1  A29-B1-C1  A40-B1-C1  A8-B1-C1 A19-B1-C1  A30-B1-C1  A41-B1-C1  A9-B1-C1 A20-B1-C1  A31-B1-C1  A42-B1-C1  A10-B1-C1  A21-B1-C1  A32-B1-C1  A43-B1-C1  A11-B1-C1  A22-B1-C1  A33-B1-C1  A44-B1-C1  A45-B1-C1  A35-B2-C1  A25-B3-C1  A15-B4-C1  A46-B1-C1  A36-B2-C1  A26-B3-C1  A16-B4-C1  A47-B1-C1  A37-B2-C1  A27-B3-C1  A17-B4-C1  A48-B1-C1  A38-B2-C1  A28-B3-C1  A18-B4-C1  A49-B1-C1  A39-B2-C1  A29-B3-C1  A19-B4-C1  A50-B1-C1  A40-B2-C1  A30-B3-C1  A20-B4-C1  A51-B1-C1  A41-B2-C1  A31-B3-C1  A21-B4-C1  A52-B1-C1  A42-B2-C1  A32-B3-C1  A22-B4-C1  A53-B1-C1  A43-B2-C1  A33-B3-C1  A23-B4-C1  A54-B1-C1  A44-B2-C1  A34-B3-C1  A24-B4-C1  A55-B1-C1  A45-B2-C1  A35-B3-C1  A25-B4-C1  A56-B1-C1  A46-B2-C1  A36-B3-C1  A26-B4-C1  A57-B1-C1  A47-B2-C1  A37-B3-C1  A27-B4-C1  A58-B1-C1  A48-B2-C1  A38-B3-C1  A28-B4-C1  A59-B1-C1  A49-B2-C1  A39-B3-C1  A29-B4-C1  A60-B1-C1  A50-B2-C1  A40-B3-C1  A30-B4-C1  A61-B1-C1  A51-B2-C1  A41-B3-C1  A31-B4-C1  A62-B1-C1  A52-B2-C1  A42-B3-C1  A32-B4-C1  A63-B1-C1  A53-B2-C1  A43-B3-C1  A33-B4-C1  A64-B1-C1  A54-B2-C1  A44-B3-C1  A34-B4-C1  A65-B1-C1  A55-B2-C1  A45-B3-C1  A35-B4-C1  A66-B1-C1  A56-B2-C1  A46-B3-C1  A36-B4-C1  A67-B1-C1  A57-B2-C1  A47-B3-C1  A37-B4-C1  A68-B1-C1  A58-B2-C1  A48-B3-C1  A38-B4-C1  A69-B1-C1  A59-B2-C1  A49-B3-C1  A39-B4-C1  A70-B1-C1  A60-B2-C1  A50-B3-C1  A40-B4-C1  A71-B1-C1  A61-B2-C1  A51-B3-C1  A41-B4-C1  A72-B1-C1  A62-B2-C1  A52-B3-C1  A42-B4-C1  A73-B1-C1  A63-B2-C1  A53-B3-C1  A43-B4-C1  A74-B1-C1  A64-B2-C1  A54-B3-C1  A44-B4-C1  A75-B1-C1  A65-B2-C1  A55-B3-C1  A45-B4-C1  A76-B1-C1  A66-B2-C1  A56-B3-C1  A46-B4-C1  A77-B1-C1  A67-B2-C1  A57-B3-C1  A47-B4-C1  A1-B2-C1 A68-B2-C1  A58-B3-C1  A48-B4-C1  A2-B2-C1 A69-B2-C1  A59-B3-C1  A49-B4-C1  A3-B2-C1 A70-B2-C1  A60-B3-C1  A50-B4-C1  A4-B2-C1 A71-B2-C1  A61-B3-C1  A51-B4-C1  A5-B2-C1 A72-B2-C1  A62-B3-C1  A52-B4-C1  A6-B2-C1 A73-B2-C1  A63-B3-C1  A53-B4-C1  A7-B2-C1 A74-B2-C1  A64-B3-C1  A54-B4-C1  A8-B2-C1 A75-B2-C1  A65-B3-C1  A55-B4-C1  A9-B2-C1 A76-B2-C1  A66-B3-C1  A56-B4-C1  A10-B2-C1  A77-B2-C1  A67-B3-C1  A57-B4-C1  A11-B2-C1  A1-B3-C1 A68-B3-C1  A58-B4-C1  A12-B2-C1  A2-B3-C1 A69-B3-C1  A59-B4-C1  A13-B2-C1  A3-B3-C1 A70-B3-C1  A60-B4-C1  A14-B2-C1  A4-B3-C1 A71-B3-C1  A61-B4-C1  A15-B2-C1  A5-B3-C1 A72-B3-C1  A62-B4-C1  A16-B2-C1  A6-B3-C1 A73-B3-C1  A63-B4-C1  A17-B2-C1  A7-B3-C1 A74-B3-C1  A64-B4-C1  A18-B2-C1  A8-B3-C1 A75-B3-C1  A65-B4-C1  A19-B2-C1  A9-B3-C1 A76-B3-C1  A66-B4-C1  A20-B2-C1  A10-B3-C1  A77-B3-C1  A67-B4-C1  A21-B2-C1  A11-B3-C1  A1-B4-C1 A68-B4-C1  A22-B2-C1  A12-B3-C1  A2-B4-C1 A69-B4-C1  A23-B2-C1  A13-B3-C1  A3-B4-C1 A70-B4-C1  A24-B2-C1  A14-B3-C1  A4-B4-C1 A71-B4-C1  A25-B2-C1  A15-B3-C1  A5-B4-C1 A72-B4-C1  A26-B2-C1  A16-B3-C1  A6-B4-C1 A73-B4-C1  A27-B2-C1  A17-B3-C1  A7-B4-C1 A74-B4-C1  A28-B2-C1  A18-B3-C1  A8-B4-C1 A75-B4-C1  A29-B2-C1  A19-B3-C1  A9-B4-C1 A76-B4-C1  A30-B2-C1  A20-B3-C1  A10-B4-C1  A77-B4-C1  A31-B2-C1  A21-B3-C1  A11-B4-C1  A1-B1-C2 A32-B2-C1  A22-B3-C1  A12-B4-C1  A2-B1-C2 A33-B2-C1  A23-B3-C1  A13-B4-C1  A3-B1-C2 A34-B2-C1  A24-B3-C1  A14-B4-C1  A4-B1-C2 A5-B1-C2 A72-B1-C2  A62-B2-C2  A52-B3-C2  A6-B1-C2 A73-B1-C2  A63-B2-C2  A53-B3-C2  A7-B1-C2 A74-B1-C2  A64-B2-C2  A54-B3-C2  A8-B1-C2 A75-B1-C2  A65-B2-C2  A55-B3-C2  A9-B1-C2 A76-B1-C2  A66-B2-C2  A56-B3-C2  A10-B1-C2  A77-B1-C2  A67-B2-C2  A57-B3-C2  A11-B1-C2  A1-B2-C2 A68-B2-C2  A58-B3-C2  A12-B1-C2  A2-B2-C2 A69-B2-C2  A59-B3-C2  A13-B1-C2  A3-B2-C2 A70-B2-C2  A60-B3-C2  A14-B1-C2  A4-B2-C2 A71-B2-C2  A61-B3-C2  A15-B1-C2  A5-B2-C2 A72-B2-C2  A62-B3-C2  A16-B1-C2  A6-B2-C2 A73-B2-C2  A63-B3-C2  A17-B1-C2  A7-B2-C2 A74-B2-C2  A64-B3-C2  A18-B1-C2  A8-B2-C2 A75-B2-C2  A65-B3-C2  A19-B1-C2  A9-B2-C2 A76-B2-C2  A66-B3-C2  A20-B1-C2  A10-B2-C2  A77-B2-C2  A67-B3-C2  A21-B1-C2  A11-B2-C2  A1-B3-C2 A68-B3-C2  A22-B1-C2  A12-B2-C2  A2-B3-C2 A69-B3-C2  A23-B1-C2  A13-B2-C2  A3-B3-C2 A70-B3-C2  A24-B1-C2  A14-B2-C2  A4-B3-C2 A71-B3-C2  A25-B1-C2  A15-B2-C2  A5-B3-C2 A72-B3-C2  A26-B1-C2  A16-B2-C2  A6-B3-C2 A73-B3-C2  A27-B1-C2  A17-B2-C2  A7-B3-C2 A74-B3-C2  A28-B1-C2  A18-B2-C2  A8-B3-C2 A75-B3-C2  A29-B1-C2  A19-B2-C2  A9-B3-C2 A76-B3-C2  A30-B1-C2  A20-B2-C2  A10-B3-C2  A77-B3-C2  A31-B1-C2  A21-B2-C2  A11-B3-C2  A1-B4-C2 A32-B1-C2  A22-B2-C2  A12-B3-C2  A2-B4-C2 A33-B1-C2  A23-B2-C2  A13-B3-C2  A3-B4-C2 A34-B1-C2  A24-B2-C2  A14-B3-C2  A4-B4-C2 A35-B1-C2  A25-B2-C2  A15-B3-C2  A5-B4-C2 A36-B1-C2  A26-B2-C2  A16-B3-C2  A6-B4-C2 A37-B1-C2  A27-B2-C2  A17-B3-C2  A7-B4-C2 A38-B1-C2  A28-B2-C2  A18-B3-C2  A8-B4-C2 A39-B1-C2  A29-B2-C2  A19-B3-C2  A9-B4-C2 A40-B1-C2  A30-B2-C2  A20-B3-C2  A10-B4-C2  A41-B1-C2  A31-B2-C2  A21-B3-C2  A11-B4-C2  A42-B1-C2  A32-B2-C2  A22-B3-C2  A12-B4-C2  A43-B1-C2  A33-B2-C2  A23-B3-C2  A13-B4-C2  A44-B1-C2  A34-B2-C2  A24-B3-C2  A14-B4-C2  A45-B1-C2  A35-B2-C2  A25-B3-C2  A15-B4-C2  A46-B1-C2  A36-B2-C2  A26-B3-C2  A16-B4-C2  A47-B1-C2  A37-B2-C2  A27-B3-C2  A17-B4-C2  A48-B1-C2  A38-B2-C2  A28-B3-C2  A18-B4-C2  A49-B1-C2  A39-B2-C2  A29-B3-C2  A19-B4-C2  A50-B1-C2  A40-B2-C2  A30-B3-C2  A20-B4-C2  A51-B1-C2  A41-B2-C2  A31-B3-C2  A21-B4-C2  A52-B1-C2  A42-B2-C2  A32-B3-C2  A22-B4-C2  A53-B1-C2  A43-B2-C2  A33-B3-C2  A23-B4-C2  A54-B1-C2  A44-B2-C2  A34-B3-C2  A24-B4-C2  A55-B1-C2  A45-B2-C2  A35-B3-C2  A25-B4-C2  A56-B1-C2  A46-B2-C2  A36-B3-C2  A26-B4-C2  A57-B1-C2  A47-B2-C2  A37-B3-C2  A27-B4-C2  A58-B1-C2  A48-B2-C2  A38-B3-C2  A28-B4-C2  A59-B1-C2  A49-B2-C2  A39-B3-C2  A29-B4-C2  A60-B1-C2  A50-B2-C2  A40-B3-C2  A30-B4-C2  A61-B1-C2  A51-B2-C2  A41-B3-C2  A31-B4-C2  A62-B1-C2  A52-B2-C2  A42-B3-C2  A32-B4-C2  A63-B1-C2  A53-B2-C2  A43-B3-C2  A33-B4-C2  A64-B1-C2  A54-B2-C2  A44-B3-C2  A34-B4-C2  A65-B1-C2  A55-B2-C2  A45-B3-C2  A35-B4-C2  A66-B1-C2  A56-B2-C2  A46-B3-C2  A36-B4-C2  A67-B1-C2  A57-B2-C2  A47-B3-C2  A37-B4-C2  A68-B1-C2  A58-B2-C2  A48-B3-C2  A38-B4-C2  A69-B1-C2  A59-B2-C2  A49-B3-C2  A39-B4-C2  A70-B1-C2  A60-B2-C2  A50-B3-C2  A40-B4-C2  A71-B1-C2  A61-B2-C2  A51-B3-C2  A41-B4-C2  A42-B4-C2  A32-B1-C3  A22-B2-C3  A12-B3-C3  A43-B4-C2  A33-B1-C3  A23-B2-C3  A13-B3-C3  A44-B4-C2  A34-B1-C3  A24-B2-C3  A14-B3-C3  A45-B4-C2  A35-B1-C3  A25-B2-C3  A15-B3-C3  A46-B4-C2  A36-B1-C3  A26-B2-C3  A16-B3-C3  A47-B4-C2  A37-B1-C3  A27-B2-C3  A17-B3-C3  A48-B4-C2  A38-B1-C3  A28-B2-C3  A18-B3-C3  A49-B4-C2  A39-B1-C3  A29-B2-C3  A19-B3-C3  A50-B4-C2  A40-B1-C3  A30-B2-C3  A20-B3-C3  A51-B4-C2  A41-B1-C3  A31-B2-C3  A21-B3-C3  A52-B4-C2  A42-B1-C3  A32-B2-C3  A22-B3-C3  A53-B4-C2  A43-B1-C3  A33-B2-C3  A23-B3-C3  A54-B4-C2  A44-B1-C3  A34-B2-C3  A24-B3-C3  A55-B4-C2  A45-B1-C3  A35-B2-C3  A25-B3-C3  A56-B4-C2  A46-B1-C3  A36-B2-C3  A26-B3-C3  A57-B4-C2  A47-B1-C3  A37-B2-C3  A27-B3-C3  A58-B4-C2  A48-B1-C3  A38-B2-C3  A28-B3-C3  A59-B4-C2  A49-B1-C3  A39-B2-C3  A29-B3-C3  A60-B4-C2  A50-B1-C3  A40-B2-C3  A30-B3-C3  A61-B4-C2  A51-B1-C3  A41-B2-C3  A31-B3-C3  A62-B4-C2  A52-B1-C3  A42-B2-C3  A32-B3-C3  A63-B4-C2  A53-B1-C3  A43-B2-C3  A33-B3-C3  A64-B4-C2  A54-B1-C3  A44-B2-C3  A34-B3-C3  A65-B4-C2  A55-B1-C3  A45-B2-C3  A35-B3-C3  A66-B4-C2  A56-B1-C3  A46-B2-C3  A36-B3-C3  A67-B4-C2  A57-B1-C3  A47-B2-C3  A37-B3-C3  A68-B4-C2  A58-B1-C3  A48-B2-C3  A38-B3-C3  A69-B4-C2  A59-B1-C3  A49-B2-C3  A39-B3-C3  A70-B4-C2  A60-B1-C3  A50-B2-C3  A40-B3-C3  A71-B4-C2  A61-B1-C3  A51-B2-C3  A41-B3-C3  A72-B4-C2  A62-B1-C3  A52-B2-C3  A42-B3-C3  A73-B4-C2  A63-B1-C3  A53-B2-C3  A43-B3-C3  A74-B4-C2  A64-B1-C3  A54-B2-C3  A44-B3-C3  A75-B4-C2  A65-B1-C3  A55-B2-C3  A45-B3-C3  A76-B4-C2  A66-B1-C3  A56-B2-C3  A46-B3-C3  A77-B4-C2  A67-B1-C3  A57-B2-C3  A47-B3-C3  A1-B1-C3 A68-B1-C3  A58-B2-C3  A48-B3-C3  A2-B1-C3 A69-B1-C3  A59-B2-C3  A49-B3-C3  A3-B1-C3 A70-B1-C3  A60-B2-C3  A50-B3-C3  A4-B1-C3 A71-B1-C3  A61-B2-C3  A51-B3-C3  A5-B1-C3 A72-B1-C3  A62-B2-C3  A52-B3-C3  A6-B1-C3 A73-B1-C3  A63-B2-C3  A53-B3-C3  A7-B1-C3 A74-B1-C3  A64-B2-C3  A54-B3-C3  A8-B1-C3 A75-B1-C3  A65-B2-C3  A55-B3-C3  A9-B1-C3 A76-B1-C3  A66-B2-C3  A56-B3-C3  A10-B1-C3  A77-B1-C3  A67-B2-C3  A57-B3-C3  A11-B1-C3  A1-B2-C3 A68-B2-C3  A58-B3-C3  A12-B1-C3  A2-B2-C3 A69-B2-C3  A59-B3-C3  A13-B1-C3  A3-B2-C3 A70-B2-C3  A60-B3-C3  A14-B1-C3  A4-B2-C3 A71-B2-C3  A61-B3-C3  A15-B1-C3  A5-B2-C3 A72-B2-C3  A62-B3-C3  A16-B1-C3  A6-B2-C3 A73-B2-C3  A63-B3-C3  A17-B1-C3  A7-B2-C3 A74-B2-C3  A64-B3-C3  A18-B1-C3  A8-B2-C3 A75-B2-C3  A65-B3-C3  A19-B1-C3  A9-B2-C3 A76-B2-C3  A66-B3-C3  A20-B1-C3  A10-B2-C3  A77-B2-C3  A67-B3-C3  A21-B1-C3  A11-B2-C3  A1-B3-C3 A68-B3-C3  A22-B1-C3  A12-B2-C3  A2-B3-C3 A69-B3-C3  A23-B1-C3  A13-B2-C3  A3-B3-C3 A70-B3-C3  A24-B1-C3  A14-B2-C3  A4-B3-C3 A71-B3-C3  A25-B1-C3  A15-B2-C3  A5-B3-C3 A72-B3-C3  A26-B1-C3  A16-B2-C3  A6-B3-C3 A73-B3-C3  A27-B1-C3  A17-B2-C3  A7-B3-C3 A74-B3-C3  A28-B1-C3  A18-B2-C3  A8-B3-C3 A75-B3-C3  A29-B1-C3  A19-B2-C3  A9-B3-C3 A76-B3-C3  A30-B1-C3  A20-B2-C3  A10-B3-C3  A77-B3-C3  A31-B1-C3  A21-B2-C3  A11-B3-C3  A1-B4-C3 A2-B4-C3 A69-B4-C3  A59-B1-C4  A49-B2-C4  A3-B4-C3 A70-B4-C3  A60-B1-C4  A50-B2-C4  A4-B4-C3 A71-B4-C3  A61-B1-C4  A51-B2-C4  A5-B4-C3 A72-B4-C3  A62-B1-C4  A52-B2-C4  A6-B4-C3 A73-B4-C3  A63-B1-C4  A53-B2-C4  A7-B4-C3 A74-B4-C3  A64-B1-C4  A54-B2-C4  A8-B4-C3 A75-B4-C3  A65-B1-C4  A55-B2-C4  A9-B4-C3 A76-B4-C3  A66-B1-C4  A56-B2-C4  A10-B4-C3  A77-B4-C3  A67-B1-C4  A57-B2-C4  A11-B4-C3  A1-B1-C4 A68-B1-C4  A58-B2-C4  A12-B4-C3  A2-B1-C4 A69-B1-C4  A59-B2-C4  A13-B4-C3  A3-B1-C4 A70-B1-C4  A60-B2-C4  A14-B4-C3  A4-B1-C4 A71-B1-C4  A61-B2-C4  A15-B4-C3  A5-B1-C4 A72-B1-C4  A62-B2-C4  A16-B4-C3  A6-B1-C4 A73-B1-C4  A63-B2-C4  A17-B4-C3  A7-B1-C4 A74-B1-C4  A64-B2-C4  A18-B4-C3  A8-B1-C4 A75-B1-C4  A65-B2-C4  A19-B4-C3  A9-B1-C4 A76-B1-C4  A66-B2-C4  A20-B4-C3  A10-B1-C4  A77-B1-C4  A67-B2-C4  A21-B4-C3  A11-B1-C4  A1-B2-C4 A68-B2-C4  A22-B4-C3  A12-B1-C4  A2-B2-C4 A69-B2-C4  A23-B4-C3  A13-B1-C4  A3-B2-C4 A70-B2-C4  A24-B4-C3  A14-B1-C4  A4-B2-C4 A71-B2-C4  A25-B4-C3  A15-B1-C4  A5-B2-C4 A72-B2-C4  A26-B4-C3  A16-B1-C4  A6-B2-C4 A73-B2-C4  A27-B4-C3  A17-B1-C4  A7-B2-C4 A74-B2-C4  A28-B4-C3  A18-B1-C4  A8-B2-C4 A75-B2-C4  A29-B4-C3  A19-B1-C4  A9-B2-C4 A76-B2-C4  A30-B4-C3  A20-B1-C4  A10-B2-C4  A77-B2-C4  A31-B4-C3  A21-B1-C4  A11-B2-C4  A1-B3-C4 A32-B4-C3  A22-B1-C4  A12-B2-C4  A2-B3-C4 A33-B4-C3  A23-B1-C4  A13-B2-C4  A3-B3-C4 A34-B4-C3  A24-B1-C4  A14-B2-C4  A4-B3-C4 A35-B4-C3  A25-B1-C4  A15-B2-C4  A5-B3-C4 A36-B4-C3  A26-B1-C4  A16-B2-C4  A6-B3-C4 A37-B4-C3  A27-B1-C4  A17-B2-C4  A7-B3-C4 A38-B4-C3  A28-B1-C4  A18-B2-C4  A8-B3-C4 A39-B4-C3  A29-B1-C4  A19-B2-C4  A9-B3-C4 A40-B4-C3  A30-B1-C4  A20-B2-C4  A10-B3-C4  A41-B4-C3  A31-B1-C4  A21-B2-C4  A11-B3-C4  A42-B4-C3  A32-B1-C4  A22-B2-C4  A12-B3-C4  A43-B4-C3  A33-B1-C4  A23-B2-C4  A13-B3-C4  A44-B4-C3  A34-B1-C4  A24-B2-C4  A14-B3-C4  A45-B4-C3  A35-B1-C4  A25-B2-C4  A15-B3-C4  A46-B4-C3  A36-B1-C4  A26-B2-C4  A16-B3-C4  A47-B4-C3  A37-B1-C4  A27-B2-C4  A17-B3-C4  A48-B4-C3  A38-B1-C4  A28-B2-C4  A18-B3-C4  A49-B4-C3  A39-B1-C4  A29-B2-C4  A19-B3-C4  A50-B4-C3  A40-B1-C4  A30-B2-C4  A20-B3-C4  A51-B4-C3  A41-B1-C4  A31-B2-C4  A21-B3-C4  A52-B4-C3  A42-B1-C4  A32-B2-C4  A22-B3-C4  A53-B4-C3  A43-B1-C4  A33-B2-C4  A23-B3-C4  A54-B4-C3  A44-B1-C4  A34-B2-C4  A24-B3-C4  A55-B4-C3  A45-B1-C4  A35-B2-C4  A25-B3-C4  A56-B4-C3  A46-B1-C4  A36-B2-C4  A26-B3-C4  A57-B4-C3  A47-B1-C4  A37-B2-C4  A27-B3-C4  A58-B4-C3  A48-B1-C4  A38-B2-C4  A28-B3-C4  A59-B4-C3  A49-B1-C4  A39-B2-C4  A29-B3-C4  A60-B4-C3  A50-B1-C4  A40-B2-C4  A30-B3-C4  A61-B4-C3  A51-B1-C4  A41-B2-C4  A31-B3-C4  A62-B4-C3  A52-B1-C4  A42-B2-C4  A32-B3-C4  A63-B4-C3  A53-B1-C4  A43-B2-C4  A33-B3-C4  A64-B4-C3  A54-B1-C4  A44-B2-C4  A34-B3-C4  A65-B4-C3  A55-B1-C4  A45-B2-C4  A35-B3-C4  A66-B4-C3  A56-B1-C4  A46-B2-C4  A36-B3-C4  A67-B4-C3  A57-B1-C4  A47-B2-C4  A37-B3-C4  A68-B4-C3  A58-B1-C4  A48-B2-C4  A38-B3-C4  A39-B3-C4  A29-B4-C4  A19-B1-C5  A9-B2-C5 A40-B3-C4  A30-B4-C4  A20-B1-C5  A10-B2-C5  A41-B3-C4  A31-B4-C4  A21-B1-C5  A11-B2-C5  A42-B3-C4  A32-B4-C4  A22-B1-C5  A12-B2-C5  A43-B3-C4  A33-B4-C4  A23-B1-C5  A13-B2-C5  A44-B3-C4  A34-B4-C4  A24-B1-C5  A14-B2-C5  A45-B3-C4  A35-B4-C4  A25-B1-C5  A15-B2-C5  A46-B3-C4  A36-B4-C4  A26-B1-C5  A16-B2-C5  A47-B3-C4  A37-B4-C4  A27-B1-C5  A17-B2-C5  A48-B3-C4  A38-B4-C4  A28-B1-C5  A18-B2-C5  A49-B3-C4  A39-B4-C4  A29-B1-C5  A19-B2-C5  A50-B3-C4  A40-B4-C4  A30-B1-C5  A20-B2-C5  A51-B3-C4  A41-B4-C4  A31-B1-C5  A21-B2-C5  A52-B3-C4  A42-B4-C4  A32-B1-C5  A22-B2-C5  A53-B3-C4  A43-B4-C4  A33-B1-C5  A23-B2-C5  A54-B3-C4  A44-B4-C4  A34-B1-C5  A24-B2-C5  A55-B3-C4  A45-B4-C4  A35-B1-C5  A25-B2-C5  A56-B3-C4  A46-B4-C4  A36-B1-C5  A26-B2-C5  A57-B3-C4  A47-B4-C4  A37-B1-C5  A27-B2-C5  A58-B3-C4  A48-B4-C4  A38-B1-C5  A28-B2-C5  A59-B3-C4  A49-B4-C4  A39-B1-C5  A29-B2-C5  A60-B3-C4  A50-B4-C4  A40-B1-C5  A30-B2-C5  A61-B3-C4  A51-B4-C4  A41-B1-C5  A31-B2-C5  A62-B3-C4  A52-B4-C4  A42-B1-C5  A32-B2-C5  A63-B3-C4  A53-B4-C4  A43-B1-C5  A33-B2-C5  A64-B3-C4  A54-B4-C4  A44-B1-C5  A34-B2-C5  A65-B3-C4  A55-B4-C4  A45-B1-C5  A35-B2-C5  A66-B3-C4  A56-B4-C4  A46-B1-C5  A36-B2-C5  A67-B3-C4  A57-B4-C4  A47-B1-C5  A37-B2-C5  A68-B3-C4  A58-B4-C4  A48-B1-C5  A38-B2-C5  A69-B3-C4  A59-B4-C4  A49-B1-C5  A39-B2-C5  A70-B3-C4  A60-B4-C4  A50-B1-C5  A40-B2-C5  A71-B3-C4  A61-B4-C4  A51-B1-C5  A41-B2-C5  A72-B3-C4  A62-B4-C4  A52-B1-C5  A42-B2-C5  A73-B3-C4  A63-B4-C4  A53-B1-C5  A43-B2-C5  A74-B3-C4  A64-B4-C4  A54-B1-C5  A44-B2-C5  A75-B3-C4  A65-B4-C4  A55-B1-C5  A45-B2-C5  A76-B3-C4  A66-B4-C4  A56-B1-C5  A46-B2-C5  A77-B3-C4  A67-B4-C4  A57-B1-C5  A47-B2-C5  A1-B4-C4 A68-B4-C4  A58-B1-C5  A48-B2-C5  A2-B4-C4 A69-B4-C4  A59-B1-C5  A49-B2-C5  A3-B4-C4 A70-B4-C4  A60-B1-C5  A50-B2-C5  A4-B4-C4 A71-B4-C4  A61-B1-C5  A51-B2-C5  A5-B4-C4 A72-B4-C4  A62-B1-C5  A52-B2-C5  A6-B4-C4 A73-B4-C4  A63-B1-C5  A53-B2-C5  A7-B4-C4 A74-B4-C4  A64-B1-C5  A54-B2-C5  A8-B4-C4 A75-B4-C4  A65-B1-C5  A55-B2-C5  A9-B4-C4 A76-B4-C4  A66-B1-C5  A56-B2-C5  A10-B4-C4  A77-B4-C4  A67-B1-C5  A57-B2-C5  A11-B4-C4  A1-B1-C5 A68-B1-C5  A58-B2-C5  A12-B4-C4  A2-B1-C5 A69-B1-C5  A59-B2-C5  A13-B4-C4  A3-B1-C5 A70-B1-C5  A60-B2-C5  A14-B4-C4  A4-B1-C5 A71-B1-C5  A61-B2-C5  A15-B4-C4  A5-B1-C5 A72-B1-C5  A62-B2-C5  A16-B4-C4  A6-B1-C5 A73-B1-C5  A63-B2-C5  A17-B4-C4  A7-B1-C5 A74-B1-C5  A64-B2-C5  A18-B4-C4  A8-B1-C5 A75-B1-C5  A65-B2-C5  A19-B4-C4  A9-B1-C5 A76-B1-C5  A66-B2-C5  A20-B4-C4  A10-B1-C5  A77-B1-C5  A67-B2-C5  A21-B4-C4  A11-B1-C5  A1-B2-C5 A68-B2-C5  A22-B4-C4  A12-B1-C5  A2-B2-C5 A69-B2-C5  A23-B4-C4  A13-B1-C5  A3-B2-C5 A70-B2-C5  A24-B4-C4  A14-B1-C5  A4-B2-C5 A71-B2-C5  A25-B4-C4  A15-B1-C5  A5-B2-C5 A72-B2-C5  A26-B4-C4  A16-B1-C5  A6-B2-C5 A73-B2-C5  A27-B4-C4  A17-B1-C5  A7-B2-C5 A74-B2-C5  A28-B4-C4  A18-B1-C5  A8-B2-C5 A75-B2-C5  A76-B2-C5  A66-B3-C5  A56-B4-C5  A46-B1-C6  A77-B2-C5  A67-B3-C5  A57-B4-C5  A47-B1-C6  A1-B3-C5 A68-B3-C5  A58-B4-C5  A48-B1-C6  A2-B3-C5 A69-B3-C5  A59-B4-C5  A49-B1-C6  A3-B3-C5 A70-B3-C5  A60-B4-C5  A50-B1-C6  A4-B3-C5 A71-B3-C5  A61-B4-C5  A51-B1-C6  A5-B3-C5 A72-B3-C5  A62-B4-C5  A52-B1-C6  A6-B3-C5 A73-B3-C5  A63-B4-C5  A53-B1-C6  A7-B3-C5 A74-B3-C5  A64-B4-C5  A54-B1-C6  A8-B3-C5 A75-B3-C5  A65-B4-C5  A55-B1-C6  A9-B3-C5 A76-B3-C5  A66-B4-C5  A56-B1-C6  A10-B3-C5  A77-B3-C5  A67-B4-C5  A57-B1-C6  A11-B3-C5  A1-B4-C5 A68-B4-C5  A58-B1-C6  A12-B3-C5  A2-B4-C5 A69-B4-C5  A59-B1-C6  A13-B3-C5  A3-B4-C5 A70-B4-C5  A60-B1-C6  A14-B3-C5  A4-B4-C5 A71-B4-C5  A61-B1-C6  A15-B3-C5  A5-B4-C5 A72-B4-C5  A62-B1-C6  A16-B3-C5  A6-B4-C5 A73-B4-C5  A63-B1-C6  A17-B3-C5  A7-B4-C5 A74-B4-C5  A64-B1-C6  A18-B3-C5  A8-B4-C5 A75-B4-C5  A65-B1-C6  A19-B3-C5  A9-B4-C5 A76-B4-C5  A66-B1-C6  A20-B3-C5  A10-B4-C5  A77-B4-C5  A67-B1-C6  A21-B3-C5  A11-B4-C5  A1-B1-C6 A68-B1-C6  A22-B3-C5  A12-B4-C5  A2-B1-C6 A69-B1-C6  A23-B3-C5  A13-B4-C5  A3-B1-C6 A70-B1-C6  A24-B3-C5  A14-B4-C5  A4-B1-C6 A71-B1-C6  A25-B3-C5  A15-B4-C5  A5-B1-C6 A72-B1-C6  A26-B3-C5  A16-B4-C5  A6-B1-C6 A73-B1-C6  A27-B3-C5  A17-B4-C5  A7-B1-C6 A74-B1-C6  A28-B3-C5  A18-B4-C5  A8-B1-C6 A75-B1-C6  A29-B3-C5  A19-B4-C5  A9-B1-C6 A76-B1-C6  A30-B3-C5  A20-B4-C5  A10-B1-C6  A77-B1-C6  A31-B3-C5  A21-B4-C5  A11-B1-C6  A1-B2-C6 A32-B3-C5  A22-B4-C5  A12-B1-C6  A2-B2-C6 A33-B3-C5  A23-B4-C5  A13-B1-C6  A3-B2-C6 A34-B3-C5  A24-B4-C5  A14-B1-C6  A4-B2-C6 A35-B3-C5  A25-B4-C5  A15-B1-C6  A5-B2-C6 A36-B3-C5  A26-B4-C5  A16-B1-C6  A6-B2-C6 A37-B3-C5  A27-B4-C5  A17-B1-C6  A7-B2-C6 A38-B3-C5  A28-B4-C5  A18-B1-C6  A8-B2-C6 A39-B3-C5  A29-B4-C5  A19-B1-C6  A9-B2-C6 A40-B3-C5  A30-B4-C5  A20-B1-C6  A10-B2-C6  A41-B3-C5  A31-B4-C5  A21-B1-C6  A11-B2-C6  A42-B3-C5  A32-B4-C5  A22-B1-C6  A12-B2-C6  A43-B3-C5  A33-B4-C5  A23-B1-C6  A13-B2-C6  A44-B3-C5  A34-B4-C5  A24-B1-C6  A14-B2-C6  A45-B3-C5  A35-B4-C5  A25-B1-C6  A15-B2-C6  A46-B3-C5  A36-B4-C5  A26-B1-C6  A16-B2-C6  A47-B3-C5  A37-B4-C5  A27-B1-C6  A17-B2-C6  A48-B3-C5  A38-B4-C5  A28-B1-C6  A18-B2-C6  A49-B3-C5  A39-B4-C5  A29-B1-C6  A19-B2-C6  A50-B3-C5  A40-B4-C5  A30-B1-C6  A20-B2-C6  A51-B3-C5  A41-B4-C5  A31-B1-C6  A21-B2-C6  A52-B3-C5  A42-B4-C5  A32-B1-C6  A22-B2-C6  A53-B3-C5  A43-B4-C5  A33-B1-C6  A23-B2-C6  A54-B3-C5  A44-B4-C5  A34-B1-C6  A24-B2-C6  A55-B3-C5  A45-B4-C5  A35-B1-C6  A25-B2-C6  A56-B3-C5  A46-B4-C5  A36-B1-C6  A26-B2-C6  A57-B3-C5  A47-B4-C5  A37-B1-C6  A27-B2-C6  A58-B3-C5  A48-B4-C5  A38-B1-C6  A28-B2-C6  A59-B3-C5  A49-B4-C5  A39-B1-C6  A29-B2-C6  A60-B3-C5  A50-B4-C5  A40-B1-C6  A30-B2-C6  A61-B3-C5  A51-B4-C5  A41-B1-C6  A31-B2-C6  A62-B3-C5  A52-B4-C5  A42-B1-C6  A32-B2-C6  A63-B3-C5  A53-B4-C5  A43-B1-C6  A33-B2-C6  A64-B3-C5  A54-B4-C5  A44-B1-C6  A34-B2-C6  A65-B3-C5  A55-B4-C5  A45-B1-C6  A35-B2-C6  A36-B2-C6  A26-B3-C6  A16-B4-C6  A6-B1-C7 A37-B2-C6  A27-B3-C6  A17-B4-C6  A7-B1-C7 A38-B2-C6  A28-B3-C6  A18-B4-C6  A8-B1-C7 A39-B2-C6  A29-B3-C6  A19-B4-C6  A9-B1-C7 A40-B2-C6  A30-B3-C6  A20-B4-C6  A10-B1-C7  A41-B2-C6  A31-B3-C6  A21-B4-C6  A11-B1-C7  A42-B2-C6  A32-B3-C6  A22-B4-C6  A12-B1-C7  A43-B2-C6  A33-B3-C6  A23-B4-C6  A13-B1-C7  A44-B2-C6  A34-B3-C6  A24-B4-C6  A14-B1-C7  A45-B2-C6  A35-B3-C6  A25-B4-C6  A15-B1-C7  A46-B2-C6  A36-B3-C6  A26-B4-C6  A16-B1-C7  A47-B2-C6  A37-B3-C6  A27-B4-C6  A17-B1-C7  A48-B2-C6  A38-B3-C6  A28-B4-C6  A18-B1-C7  A49-B2-C6  A39-B3-C6  A29-B4-C6  A19-B1-C7  A50-B2-C6  A40-B3-C6  A30-B4-C6  A20-B1-C7  A51-B2-C6  A41-B3-C6  A31-B4-C6  A21-B1-C7  A52-B2-C6  A42-B3-C6  A32-B4-C6  A22-B1-C7  A53-B2-C6  A43-B3-C6  A33-B4-C6  A23-B1-C7  A54-B2-C6  A44-B3-C6  A34-B4-C6  A24-B1-C7  A55-B2-C6  A45-B3-C6  A35-B4-C6  A25-B1-C7  A56-B2-C6  A46-B3-C6  A36-B4-C6  A26-B1-C7  A57-B2-C6  A47-B3-C6  A37-B4-C6  A27-B1-C7  A58-B2-C6  A48-B3-C6  A38-B4-C6  A28-B1-C7  A59-B2-C6  A49-B3-C6  A39-B4-C6  A29-B1-C7  A60-B2-C6  A50-B3-C6  A40-B4-C6  A30-B1-C7  A61-B2-C6  A51-B3-C6  A41-B4-C6  A31-B1-C7  A62-B2-C6  A52-B3-C6  A42-B4-C6  A32-B1-C7  A63-B2-C6  A53-B3-C6  A43-B4-C6  A33-B1-C7  A64-B2-C6  A54-B3-C6  A44-B4-C6  A34-B1-C7  A65-B2-C6  A55-B3-C6  A45-B4-C6  A35-B1-C7  A66-B2-C6  A56-B3-C6  A46-B4-C6  A36-B1-C7  A67-B2-C6  A57-B3-C6  A47-B4-C6  A37-B1-C7  A68-B2-C6  A58-B3-C6  A48-B4-C6  A38-B1-C7  A69-B2-C6  A59-B3-C6  A49-B4-C6  A39-B1-C7  A70-B2-C6  A60-B3-C6  A50-B4-C6  A40-B1-C7  A71-B2-C6  A61-B3-C6  A51-B4-C6  A41-B1-C7  A72-B2-C6  A62-B3-C6  A52-B4-C6  A42-B1-C7  A73-B2-C6  A63-B3-C6  A53-B4-C6  A43-B1-C7  A74-B2-C6  A64-B3-C6  A54-B4-C6  A44-B1-C7  A75-B2-C6  A65-B3-C6  A55-B4-C6  A45-B1-C7  A76-B2-C6  A66-B3-C6  A56-B4-C6  A46-B1-C7  A77-B2-C6  A67-B3-C6  A57-B4-C6  A47-B1-C7  A1-B3-C6 A68-B3-C6  A58-B4-C6  A48-B1-C7  A2-B3-C6 A69-B3-C6  A59-B4-C6  A49-B1-C7  A3-B3-C6 A70-B3-C6  A60-B4-C6  A50-B1-C7  A4-B3-C6 A71-B3-C6  A61-B4-C6  A51-B1-C7  A5-B3-C6 A72-B3-C6  A62-B4-C6  A52-B1-C7  A6-B3-C6 A73-B3-C6  A63-B4-C6  A53-B1-C7  A7-B3-C6 A74-B3-C6  A64-B4-C6  A54-B1-C7  A8-B3-C6 A75-B3-C6  A65-B4-C6  A55-B1-C7  A9-B3-C6 A76-B3-C6  A66-B4-C6  A56-B1-C7  A10-B3-C6  A77-B3-C6  A67-B4-C6  A57-B1-C7  A11-B3-C6  A1-B4-C6 A68-B4-C6  A58-B1-C7  A12-B3-C6  A2-B4-C6 A69-B4-C6  A59-B1-C7  A13-B3-C6  A3-B4-C6 A70-B4-C6  A60-B1-C7  A14-B3-C6  A4-B4-C6 A71-B4-C6  A61-B1-C7  A15-B3-C6  A5-B4-C6 A72-B4-C6  A62-B1-C7  A16-B3-C6  A6-B4-C6 A73-B4-C6  A63-B1-C7  A17-B3-C6  A7-B4-C6 A74-B4-C6  A64-B1-C7  A18-B3-C6  A8-B4-C6 A75-B4-C6  A65-B1-C7  A19-B3-C6  A9-B4-C6 A76-B4-C6  A66-B1-C7  A20-B3-C6  A10-B4-C6  A77-B4-C6  A67-B1-C7  A21-B3-C6  A11-B4-C6  A1-B1-C7 A68-B1-C7  A22-B3-C6  A12-B4-C6  A2-B1-C7 A69-B1-C7  A23-B3-C6  A13-B4-C6  A3-B1-C7 A70-B1-C7  A24-B3-C6  A14-B4-C6  A4-B1-C7 A71-B1-C7  A25-B3-C6  A15-B4-C6  A5-B1-C7 A72-B1-C7  A73-B1-C7  A63-B2-C7  A53-B3-C7  A43-B4-C7  A74-B1-C7  A64-B2-C7  A54-B3-C7  A44-B4-C7  A75-B1-C7  A65-B2-C7  A55-B3-C7  A45-B4-C7  A76-B1-C7  A66-B2-C7  A56-B3-C7  A46-B4-C7  A77-B1-C7  A67-B2-C7  A57-B3-C7  A47-B4-C7  A1-B2-C7 A68-B2-C7  A58-B3-C7  A48-B4-C7  A2-B2-C7 A69-B2-C7  A59-B3-C7  A49-B4-C7  A3-B2-C7 A70-B2-C7  A60-B3-C7  A50-B4-C7  A4-B2-C7 A71-B2-C7  A61-B3-C7  A51-B4-C7  A5-B2-C7 A72-B2-C7  A62-B3-C7  A52-B4-C7  A6-B2-C7 A73-B2-C7  A63-B3-C7  A53-B4-C7  A7-B2-C7 A74-B2-C7  A64-B3-C7  A54-B4-C7  A8-B2-C7 A75-B2-C7  A65-B3-C7  A55-B4-C7  A9-B2-C7 A76-B2-C7  A66-B3-C7  A56-B4-C7  A10-B2-C7  A77-B2-C7  A67-B3-C7  A57-B4-C7  A11-B2-C7  A1-B3-C7 A68-B3-C7  A58-B4-C7  A12-B2-C7  A2-B3-C7 A69-B3-C7  A59-B4-C7  A13-B2-C7  A3-B3-C7 A70-B3-C7  A60-B4-C7  A14-B2-C7  A4-B3-C7 A71-B3-C7  A61-B4-C7  A15-B2-C7  A5-B3-C7 A72-B3-C7  A62-B4-C7  A16-B2-C7  A6-B3-C7 A73-B3-C7  A63-B4-C7  A17-B2-C7  A7-B3-C7 A74-B3-C7  A64-B4-C7  A18-B2-C7  A8-B3-C7 A75-B3-C7  A65-B4-C7  A19-B2-C7  A9-B3-C7 A76-B3-C7  A66-B4-C7  A20-B2-C7  A10-B3-C7  A77-B3-C7  A67-B4-C7  A21-B2-C7  A11-B3-C7  A1-B4-C7 A68-B4-C7  A22-B2-C7  A12-B3-C7  A2-B4-C7 A69-B4-C7  A23-B2-C7  A13-B3-C7  A3-B4-C7 A70-B4-C7  A24-B2-C7  A14-B3-C7  A4-B4-C7 A71-B4-C7  A25-B2-C7  A15-B3-C7  A5-B4-C7 A72-B4-C7  A26-B2-C7  A16-B3-C7  A6-B4-C7 A73-B4-C7  A27-B2-C7  A17-B3-C7  A7-B4-C7 A74-B4-C7  A28-B2-C7  A18-B3-C7  A8-B4-C7 A75-B4-C7  A29-B2-C7  A19-B3-C7  A9-B4-C7 A76-B4-C7  A30-B2-C7  A20-B3-C7  A10-B4-C7  A77-B4-C7  A31-B2-C7  A21-B3-C7  A11-B4-C7  A1-B1-C8 A32-B2-C7  A22-B3-C7  A12-B4-C7  A2-B1-C8 A33-B2-C7  A23-B3-C7  A13-B4-C7  A3-B1-C8 A34-B2-C7  A24-B3-C7  A14-B4-C7  A4-B1-C8 A35-B2-C7  A25-B3-C7  A15-B4-C7  A5-B1-C8 A36-B2-C7  A26-B3-C7  A16-B4-C7  A6-B1-C8 A37-B2-C7  A27-B3-C7  A17-B4-C7  A7-B1-C8 A38-B2-C7  A28-B3-C7  A18-B4-C7  A8-B1-C8 A39-B2-C7  A29-B3-C7  A19-B4-C7  A9-B1-C8 A40-B2-C7  A30-B3-C7  A20-B4-C7  A10-B1-C8  A41-B2-C7  A31-B3-C7  A21-B4-C7  A11-B1-C8  A42-B2-C7  A32-B3-C7  A22-B4-C7  A12-B1-C8  A43-B2-C7  A33-B3-C7  A23-B4-C7  A13-B1-C8  A44-B2-C7  A34-B3-C7  A24-B4-C7  A14-B1-C8  A45-B2-C7  A35-B3-C7  A25-B4-C7  A15-B1-C8  A46-B2-C7  A36-B3-C7  A26-B4-C7  A16-B1-C8  A47-B2-C7  A37-B3-C7  A27-B4-C7  A17-B1-C8  A48-B2-C7  A38-B3-C7  A28-B4-C7  A18-B1-C8  A49-B2-C7  A39-B3-C7  A29-B4-C7  A19-B1-C8  A50-B2-C7  A40-B3-C7  A30-B4-C7  A20-B1-C8  A51-B2-C7  A41-B3-C7  A31-B4-C7  A21-B1-C8  A52-B2-C7  A42-B3-C7  A32-B4-C7  A22-B1-C8  A53-B2-C7  A43-B3-C7  A33-B4-C7  A23-B1-C8  A54-B2-C7  A44-B3-C7  A34-B4-C7  A24-B1-C8  A55-B2-C7  A45-B3-C7  A35-B4-C7  A25-B1-C8  A56-B2-C7  A46-B3-C7  A36-B4-C7  A26-B1-C8  A57-B2-C7  A47-B3-C7  A37-B4-C7  A27-B1-C8  A58-B2-C7  A48-B3-C7  A38-B4-C7  A28-B1-C8  A59-B2-C7  A49-B3-C7  A39-B4-C7  A29-B1-C8  A60-B2-C7  A50-B3-C7  A40-B4-C7  A30-B1-C8  A61-B2-C7  A51-B3-C7  A41-B4-C7  A31-B1-C8  A62-B2-C7  A52-B3-C7  A42-B4-C7  A32-B1-C8  A33-B1-C8  A23-B2-C8  A13-B3-C8  A3-B4-C8 A34-B1-C8  A24-B2-C8  A14-B3-C8  A4-B4-C8 A35-B1-C8  A25-B2-C8  A15-B3-C8  A5-B4-C8 A36-B1-C8  A26-B2-C8  A16-B3-C8  A6-B4-C8 A37-B1-C8  A27-B2-C8  A17-B3-C8  A7-B4-C8 A38-B1-C8  A28-B2-C8  A18-B3-C8  A8-B4-C8 A39-B1-C8  A29-B2-C8  A19-B3-C8  A9-B4-C8 A40-B1-C8  A30-B2-C8  A20-B3-C8  A10-B4-C8  A41-B1-C8  A31-B2-C8  A21-B3-C8  A11-B4-C8  A42-B1-C8  A32-B2-C8  A22-B3-C8  A12-B4-C8  A43-B1-C8  A33-B2-C8  A23-B3-C8  A13-B4-C8  A44-B1-C8  A34-B2-C8  A24-B3-C8  A14-B4-C8  A45-B1-C8  A35-B2-C8  A25-B3-C8  A15-B4-C8  A46-B1-C8  A36-B2-C8  A26-B3-C8  A16-B4-C8  A47-B1-C8  A37-B2-C8  A27-B3-C8  A17-B4-C8  A48-B1-C8  A38-B2-C8  A28-B3-C8  A18-B4-C8  A49-B1-C8  A39-B2-C8  A29-B3-C8  A19-B4-C8  A50-B1-C8  A40-B2-C8  A30-B3-C8  A20-B4-C8  A51-B1-C8  A41-B2-C8  A31-B3-C8  A21-B4-C8  A52-B1-C8  A42-B2-C8  A32-B3-C8  A22-B4-C8  A53-B1-C8  A43-B2-C8  A33-B3-C8  A23-B4-C8  A54-B1-C8  A44-B2-C8  A34-B3-C8  A24-B4-C8  A55-B1-C8  A45-B2-C8  A35-B3-C8  A25-B4-C8  A56-B1-C8  A46-B2-C8  A36-B3-C8  A26-B4-C8  A57-B1-C8  A47-B2-C8  A37-B3-C8  A27-B4-C8  A58-B1-C8  A48-B2-C8  A38-B3-C8  A28-B4-C8  A59-B1-C8  A49-B2-C8  A39-B3-C8  A29-B4-CB  A60-B1-C8  A50-B2-C8  A40-B3-C8  A30-B4-C8  A61-B1-C8  A51-B2-C8  A41-B3-C8  A31-B4-C8  A62-B1-C8  A52-B2-C8  A42-B3-C8  A32-B4-C8  A63-B1-C8  A53-B2-C8  A43-B3-C8  A33-B4-C8  A64-B1-C8  A54-B2-C8  A44-B3-C8  A34-B4-C8  A65-B1-C8  A55-B2-C8  A45-B3-C8  A35-B4-C8  A66-B1-C8  A56-B2-C8  A46-B3-C8  A36-B4-C8  A67-B1-C8  A57-B2-C8  A47-B3-C8  A37-B4-C8  A68-B1-C8  A58-B2-C8  A48-B3-C8  A38-B4-C8  A69-B1-C8  A59-B2-C8  A49-B3-C8  A39-B4-C8  A70-B1-C8  A60-B2-C8  A50-B3-C8  A40-B4-C8  A71-B1-C8  A61-B2-C8  A51-B3-C8  A41-B4-C8  A72-B1-C8  A62-B2-C8  A52-B3-C8  A42-B4-C8  A73-B1-C8  A63-B2-C8  A53-B3-C8  A43-B4-C8  A74-B1-C8  A64-B2-C8  A54-B3-C8  A44-B4-C8  A75-B1-C8  A65-B2-C8  A55-B3-C8  A45-B4-C8  A76-B1-C8  A66-B2-C8  A56-B3-C8  A46-B4-C8  A77-B1-C8  A67-B2-C8  A57-B3-C8  A47-B4-C8  A1-B2-C8 A68-B2-C8  A58-B3-C8  A48-B4-C8  A2-B2-C8 A69-B2-C8  A59-B3-C8  A49-B4-C8  A3-B2-C8 A70-B2-C8  A60-B3-C8  A50-B4-C8  A4-B2-C8 A71-B2-C8  A61-B3-C8  A51-B4-C8  A5-B2-C8 A72-B2-C8  A62-B3-C8  A52-B4-C8  A6-B2-C8 A73-B2-C8  A63-B3-C8  A53-B4-C8  A7-B2-C8 A74-B2-C8  A64-B3-C8  A54-B4-C8  A8-B2-C8 A75-B2-C8  A65-B3-C8  A55-B4-C8  A9-B2-C8 A76-B2-C8  A66-B3-C8  A56-B4-C8  A10-B2-C8  A77-B2-C8  A67-B3-C8  A57-B4-C8  A11-B2-C8  A1-B3-C8 A68-B3-C8  A58-B4-C8  A12-B2-C8  A2-B3-C8 A69-B3-C8  A59-B4-C8  A13-B2-C8  A3-B3-C8 A70-B3-C8  A60-B4-C8  A14-B2-C8  A4-B3-C8 A71-B3-C8  A61-B4-C8  A15-B2-C8  A5-B3-C8 A72-B3-C8  A62-B4-C8  A16-B2-C8  A6-B3-C8 A73-B3-C8  A63-B4-C8  A17-B2-C8  A7-B3-C8 A74-B3-C8  A64-B4-C8  A18-B2-C8  A8-B3-C8 A75-B3-C8  A65-B4-C8  A19-B2-C8  A9-B3-C8 A76-B3-C8  A66-B4-C8  A20-B2-C8  A10-B3-C8  A77-B3-C8  A67-B4-C8  A21-B2-C8  A11-B3-C8  A1-B4-C8 A68-B4-C8  A22-B2-C8  A12-B3-C8  A2-B4-C8 A69-B4-C8  A70-B4-C8  A60-B1-C9  A50-B2-C9  A40-B3-C9  A71-B4-C8  A61-B1-C9  A51-B2-C9  A41-B3-C9  A72-B4-C8  A62-B1-C9  A52-B2-C9  A42-B3-C9  A73-B4-C8  A63-B1-C9  A53-B2-C9  A43-B3-C9  A74-B4-C8  A64-B1-C9  A54-B2-C9  A44-B3-C9  A75-B4-C8  A65-B1-C9  A55-B2-C9  A45-B3-C9  A76-B4-C8  A66-B1-C9  A56-B2-C9  A46-B3-C9  A77-B4-C8  A67-B1-C9  A57-B2-C9  A47-B3-C9  A1-B1-C9 A68-B1-C9  A58-B2-C9  A48-B3-C9  A2-B1-C9 A69-B1-C9  A59-B2-C9  A49-B3-C9  A3-B1-C9 A70-B1-C9  A60-B2-C9  A50-B3-C9  A4-B1-C9 A71-B1-C9  A61-B2-C9  A51-B3-C9  A5-B1-C9 A72-B1-C9  A62-B2-C9  A52-B3-C9  A6-B1-C9 A73-B1-C9  A63-B2-C9  A53-B3-C9  A7-B1-C9 A74-B1-C9  A64-B2-C9  A54-B3-C9  A8-B1-C9 A75-B1-C9  A65-B2-C9  A55-B3-C9  A9-B1-C9 A76-B1-C9  A66-B2-C9  A56-B3-C9  A10-B1-C9  A77-B1-C9  A67-B2-C9  A57-B3-C9  A11-B1-C9  A1-B2-C9 A68-B2-C9  A58-B3-C9  A12-B1-C9  A2-B2-C9 A69-B2-C9  A59-B3-C9  A13-B1-C9  A3-B2-C9 A70-B2-C9  A60-B3-C9  A14-B1-C9  A4-B2-C9 A71-B2-C9  A61-B3-C9  A15-B1-C9  A5-B2-C9 A72-B2-C9  A62-B3-C9  A16-B1-C9  A6-B2-C9 A73-B2-C9  A63-B3-C9  A17-B1-C9  A7-B2-C9 A74-B2-C9  A64-B3-C9  A18-B1-C9  A8-B2-C9 A75-B2-C9  A65-B3-C9  A19-B1-C9  A9-B2-C9 A76-B2-C9  A66-B3-C9  A20-B1-C9  A10-B2-C9  A77-B2-C9  A67-B3-C9  A21-B1-C9  A11-B2-C9  A1-B3-C9 A68-B3-C9  A22-B1-C9  A12-B2-C9  A2-B3-C9 A69-B3-C9  A23-B1-C9  A13-B2-C9  A3-B3-C9 A70-B3-C9  A24-B1-C9  A14-B2-C9  A4-B3-C9 A71-B3-C9  A25-B1-C9  A15-B2-C9  A5-B3-C9 A72-B3-C9  A26-B1-C9  A16-B2-C9  A6-B3-C9 A73-B3-C9  A27-B1-C9  A17-B2-C9  A7-B3-C9 A74-B3-C9  A28-B1-C9  A18-B2-C9  A8-B3-C9 A75-B3-C9  A29-B1-C9  A19-B2-C9  A9-B3-C9 A76-B3-C9  A30-B1-C9  A20-B2-C9  A10-B3-C9  A77-B3-C9  A31-B1-C9  A21-B2-C9  A11-B3-C9  A1-B4-C9 A32-B1-C9  A22-B2-C9  A12-B3-C9  A2-B4-C9 A33-B1-C9  A23-B2-C9  A13-B3-C9  A3-B4-C9 A34-B1-C9  A24-B2-C9  A14-B3-C9  A4-B4-C9 A35-B1-C9  A25-B2-C9  A15-B3-C9  A5-B4-C9 A36-B1-C9  A26-B2-C9  A16-B3-C9  A6-B4-C9 A37-B1-C9  A27-B2-C9  A17-B3-C9  A7-B4-C9 A38-B1-C9  A28-B2-C9  A18-B3-C9  A8-B4-C9 A39-B1-C9  A29-B2-C9  A19-B3-C9  A9-B4-C9 A40-B1-C9  A30-B2-C9  A20-B3-C9  A10-B4-C9  A41-B1-C9  A31-B2-C9  A21-B3-C9  A11-B4-C9  A42-B1-C9  A32-B2-C9  A22-B3-C9  A12-B4-C9  A43-B1-C9  A33-B2-C9  A23-B3-C9  A13-B4-C9  A44-B1-C9  A34-B2-C9  A24-B3-C9  A14-B4-C9  A45-B1-C9  A35-B2-C9  A25-B3-C9  A15-B4-C9  A46-B1-C9  A36-B2-C9  A26-B3-C9  A16-B4-C9  A47-B1-C9  A37-B2-C9  A27-B3-C9  A17-B4-C9  A48-B1-C9  A38-B2-C9  A28-B3-C9  A18-B4-C9  A49-B1-C9  A39-B2-C9  A29-B3-C9  A19-B4-C9  A50-B1-C9  A40-B2-C9  A30-B3-C9  A20-B4-C9  A51-B1-C9  A41-B2-C9  A31-B3-C9  A21-B4-C9  A52-B1-C9  A42-B2-C9  A32-B3-C9  A22-B4-C9  A53-B1-C9  A43-B2-C9  A33-B3-C9  A23-B4-C9  A54-B1-C9  A44-B2-C9  A34-B3-C9  A24-B4-C9  A55-B1-C9  A45-B2-C9  A35-B3-C9  A25-B4-C9  A56-B1-C9  A46-B2-C9  A36-B3-C9  A26-B4-C9  A57-B1-C9  A47-B2-C9  A37-B3-C9  A27-B4-C9  A58-B1-C9  A48-B2-C9  A38-B3-C9  A28-B4-C9  A59-B1-C9  A49-B2-C9  A39-B3-C9  A29-B4-C9  A30-B4-C9  A20-B1-C10 A10-B2-C10 A77-B2-C10 A31-B4-C9  A21-B1-C10 A11-B2-C10  A1-B3-C10 A32-B4-C9  A22-B1-C10 A12-B2-C10  A2-B3-C10 A33-B4-C9  A23-B1-C10 A13-B2-C10  A3-B3-C10 A34-B4-C9  A24-B1-C10 A14-B2-C10  A4-B3-C10 A35-B4-C9  A25-B1-C10 A15-B2-C10  A5-B3-C10 A36-B4-C9  A26-B1-C10 A16-B2-C10  A6-B3-C10 A37-B4-C9  A27-B1-C10 A17-B2-C10  A7-B3-C10 A38-B4-C9  A28-B1-C10 A18-B2-C10  A8-B3-C10 A39-B4-C9  A29-B1-C10 A19-B2-C10  A9-B3-C10 A40-B4-C9  A30-B1-C10 A20-B2-C10 A10-B3-C10 A41-B4-C9  A31-B1-C10 A21-B2-C10 A11-B3-C10 A42-B4-C9  A32-B1-C10 A22-B2-C10 A12-B3-C10 A43-B4-C9  A33-B1-C10 A23-B2-C10 A13-B3-C10 A44-B4-C9  A34-B1-C10 A24-B2-C10 A14-B3-C10 A45-B4-C9  A35-B1-C10 A25-B2-C10 A15-B3-C10 A46-B4-C9  A36-B1-C10 A26-B2-C10 A16-B3-C10 A47-B4-C9  A37-B1-C10 A27-B2-C10 A17-B3-C10 A48-B4-C9  A38-B1-C10 A28-B2-C10 A18-B3-C10 A49-B4-C9  A39-B1-C10 A29-B2-C10 A19-B3-C10 A50-B4-C9  A40-B1-C10 A30-B2-C10 A20-B3-C10 A51-B4-C9  A41-B1-C10 A31-B2-C10 A21-B3-C10 A52-B4-C9  A42-B1-C10 A32-B2-C10 A22-B3-C10 A53-B4-C9  A43-B1-C10 A33-B2-C10 A23-B3-C10 A54-B4-C9  A44-B1-C10 A34-B2-C10 A24-B3-C10 A55-B4-C9  A45-B1-C10 A35-B2-C10 A25-B3-C10 A56-B4-C9  A46-B1-C10 A36-B2-C10 A26-B3-C10 A57-B4-C9  A47-B1-C10 A37-B2-C10 A27-B3-C10 A58-B4-C9  A48-B1-C10 A33-B2-C10 A28-B3-C10 A59-B4-C9  A49-B1-C10 A39-B2-C10 A29-B3-C10 A60-B4-C9  A50-B1-C10 A40-B2-C10 A30-B3-C10 A61-B4-C9  A51-B1-C10 A41-B2-C10 A31-B3-C10 A62-B4-C9  A52-B1-C10 A42-B2-C10 A32-B3-C10 A63-B4-C9  A53-B1-C10 A43-B2-C10 A33-B3-C10 A64-B4-C9  A54-B1-C10 A44-B2-C10 A34-B3-C10 A65-B4-C9  A55-B1-C10 A45-B2-C10 A35-B3-C10 A66-B4-C9  A56-B1-C10 A46-B2-C10 A36-B3-C10 A67-B4-C9  A57-B1-C10 A47-B2-C10 A37-B3-C10 A68-B4-C9  A58-B1-C10 A48-B2-C10 A38-B3-C10 A69-B4-C9  A59-B1-C10 A49-B2-C10 A39-B3-C10 A70-B4-C9  A60-B1-C10 A50-B2-C10 A40-B3-C10 A71-B4-C9  A61-B1-C10 A51-B2-C10 A41-B3-C10 A72-B4-C9  A62-B1-C10 A52-B2-C10 A42-B3-C10 A73-B4-C9  A63-B1-C10 A53-B2-C10 A43-B3-C10 A74-B4-C9  A64-B1-C10 A54-B2-C10 A44-B3-C10 A75-B4-C9  A65-B1-C10 A55-B2-C10 A45-B3-C10 A76-B4-C9  A66-B1-C10 A56-B2-C10 A46-B3-C10 A77-B4-C9  A67-B1-C10 A57-B2-C10 A47-B3-C10  A1-B1-C10 A68-B1-C10 A58-B2-C10 A48-B3-C10  A2-B1-C10 A69-B1-C10 A59-B2-C10 A49-B3-C10  A3-B1-C10 A70-B1-C10 A60-B2-C10 A50-B3-C10  A4-B1-C10 A71-B1-C10 A61-B2-C10 A51-B3-C10  A5-B1-C10 A72-B1-C10 A62-B2-C10 A52-B3-C10  A6-B1-C10 A73-B1-C10 A63-B2-C10 A53-B3-C10  A7-B1-C10 A74-B1-C10 A64-B2-C10 A54-B3-C10  A8-B1-C10 A75-B1-C10 A65-B2-C10 A55-B3-C10  A9-B1-C10 A76-B1-C10 A66-B2-C10 A56-B3-C10 A10-B1-C10 A77-B1-C10 A67-B2-C10 A57-B3-C10 A11-B1-C10  A1-B2-C10 A68-B2-C10 A58-B3-C10 A12-B1-C10  A2-B2-C10 A69-B2-C10 A59-B3-C10 A13-B1-C10  A3-B2-C10 A70-B2-C10 A60-B3-C10 A14-B1-C10  A4-B2-C10 A71-B2-C10 A61-B3-C10 A15-B1-C10  A5-B2-C10 A72-B2-C10 A62-B3-C10 A16-B1-C10  A6-B2-C10 A73-B2-C10 A63-B3-C10 A17-B1-C10  A7-B2-C10 A74-B2-C10 A64-B3-C10 A18-B1-C10  A8-B2-C10 A75-B2-C10 A65-B3-C10 A19-B1-C10  A9-B2-C10 A76-B2-C10 A66-B3-C10 A67-B3-C10 A57-B4-C10 A47-B1-C11 A37-B2-C11 A68-B3-C10 A58-B4-C10 A48-B1-C11 A38-B2-C11 A69-B3-C10 A59-B4-C10 A49-B1-C11 A39-B2-C11 A70-B3-C10 A60-B4-C10 A50-B1-C11 A40-B2-C11 A71-B3-C10 A61-B4-C10 A51-B1-C11 A41-B2-C11 A72-B3-C10 A62-B4-C10 A52-B1-C11 A42-B2-C11 A73-B3-C10 A63-B4-C10 A53-B1-C11 A43-B2-C11 A74-B3-C10 A64-B4-C10 A54-B1-C11 A44-B2-C11 A75-B3-C10 A65-B4-C10 A55-B1-C11 A45-B2-C11 A76-B3-C10 A66-B4-C10 A56-B1-C11 A46-B2-C11 A77-B3-C10 A67-B4-C10 A57-B1-C11 A47-B2-C11  A1-B4-C10 A68-B4-C10 A58-B1-C11 A48-B2-C11  A2-B4-C10 A69-B4-C10 A59-B1-C11 A49-B2-C11  A3-B4-C10 A70-B4-C10 A60-B1-C11 A50-B2-C11  A4-B4-C10 A71-B4-C10 A61-B1-C11 A51-B2-C11  A5-B4-C10 A72-B4-C10 A62-B1-C11 A52-B2-C11  A6-B4-C10 A73-B4-C10 A63-B1-C11 A53-B2-C11  A7-B4-C10 A74-B4-C10 A64-B1-C11 A54-B2-C11  A8-B4-C10 A75-B4-C10 A65-B1-C11 A55-B2-C11  A9-B4-C10 A76-B4-C10 A66-B1-C11 A56-B2-C11 A10-B4-C10 A77-B4-C10 A67-B1-C11 A57-B2-C11 A11-B4-C10  A1-B1-C11 A68-B1-C11 A58-B2-C11 A12-B4-C10  A2-B1-C11 A69-B1-C11 A59-B2-C11 A13-B4-C10  A3-B1-C11 A70-B1-C11 A60-B2-C11 A14-B4-C10  A4-B1-C11 A71-B1-C11 A61-B2-C11 A15-B4-C10  A5-B1-C11 A72-B1-C11 A62-B2-C11 A16-B4-C10  A6-B1-C11 A73-B1-C11 A63-B2-C11 A17-B4-C10  A7-B1-C11 A74-B1-C11 A64-B2-C11 A18-B4-C10  A8-B1-C11 A75-B1-C11 A65-B2-C11 A19-B4-C10  A9-B1-C11 A76-B1-C11 A66-B2-C11 A20-B4-C10 A10-B1-C11 A77-B1-C11 A67-B2-C11 A21-B4-C10 A11-B1-C11  A1-B2-C11 A68-B2-C11 A22-B4-C10 A12-B1-C11  A2-B2-C11 A69-B2-C11 A23-B4-C10 A13-B1-C11  A3-B2-C11 A70-B2-C11 A24-B4-C10 A14-B1-C11  A4-B2-C11 A71-B2-C11 A25-B4-C10 A15-B1-C11  A5-B2-C11 A72-B2-C11 A26-B4-C10 A16-B1-C11  A6-B2-C11 A73-B2-C11 A27-B4-C10 A17-B1-C11  A7-B2-C11 A74-B2-C11 A28-B4-C10 A18-B1-C11  A8-B2-C11 A75-B2-C11 A29-B4-C10 A19-B1-C11  A9-B2-C11 A76-B2-C11 A30-B4-C10 A20-B1-C11 A10-B2-C11 A77-B2-C11 A31-B4-C10 A21-B1-C11 A11-B2-C11  A1-B3-C11 A32-B4-C10 A22-B1-C11 A12-B2-C11  A2-B3-C11 A33-B4-C10 A23-B1-C11 A13-B2-C11  A3-B3-C11 A34-B4-C10 A24-B1-C11 A14-B2-C11  A4-B3-C11 A35-B4-C10 A25-B1-C11 A15-B2-C11  A5-B3-C11 A36-B4-C10 A26-B1-C11 A16-B2-C11  A6-B3-C11 A37-B4-C10 A27-B1-C11 A17-B2-C11  A7-B3-C11 A38-B4-C10 A28-B1-C11 A18-B2-C11  A8-B3-C11 A39-B4-C10 A29-B1-C11 A19-B2-C11  A9-B3-C11 A40-B4-C10 A30-B1-C11 A20-B2-C11 A10-B3-C11 A41-B4-C10 A31-B1-C11 A21-B2-C11 A11-B3-C11 A42-B4-C10 A32-B1-C11 A22-B2-C11 A12-B3-C11 A43-B4-C10 A33-B1-C11 A23-B2-C11 A13-B3-C11 A44-B4-C10 A34-B1-C11 A24-B2-C11 A14-B3-C11 A45-B4-C10 A35-B1-C11 A25-B2-C11 A15-B3-C11 A46-B4-C10 A36-B1-C11 A26-B2-C11 A16-B3-C11 A47-B4-C10 A37-B1-C11 A27-B2-C11 A17-B3-C11 A48-B4-C10 A38-B1-C11 A28-B2-C11 A18-B3-C11 A49-B4-C10 A39-B1-C11 A29-B2-C11 A19-B3-C11 A50-B4-C10 A40-B1-C11 A30-B2-C11 A20-B3-C11 A51-B4-C10 A41-B1-C11 A31-B2-C11 A21-B3-C11 A52-B4-C10 A42-B1-C11 A32-B2-C11 A22-B3-C11 A53-B4-C10 A43-B1-C11 A33-B2-C11 A23-B3-C11 A54-B4-C10 A44-B1-C11 A34-B2-C11 A24-B3-C11 A55-B4-C10 A45-B1-C11 A35-B2-C11 A25-B3-C11 A56-B4-C10 A46-B1-C11 A36-B2-C11 A26-B3-C11 A27-B3-C11 A17-B4-C11  A7-B1-C12 A74-B1-C12 A28-B3-C11 A18-B4-C11  A8-B1-C12 A75-B1-C12 A29-B3-C11 A19-B4-C11  A9-B1-C12 A76-B1-C12 A30-B3-C11 A20-B4-C11 A10-B1-C12 A77-B1-C12 A31-B3-C11 A21-B4-C11 A11-B1-C12  A1-B2-C12 A32-B3-C11 A22-B4-C11 A12-B1-C12  A2-B2-C12 A33-B3-C11 A23-B4-C11 A13-B1-C12  A3-B2-C12 A34-B3-C11 A24-B4-C11 A14-B1-C12  A4-B2-C12 A35-B3-C11 A25-B4-C11 A15-B1-C12  A5-B2-C12 A36-B3-C11 A26-B4-C11 A16-B1-C12  A6-B2-C12 A37-B3-C11 A27-B4-C11 A17-B1-C12  A7-B2-C12 A38-B3-C11 A28-B4-C11 A18-B1-C12  A8-B2-C12 A39-B3-C11 A29-B4-C11 A19-B1-C12  A9-B2-C12 A40-B3-C11 A30-B4-C11 A20-B1-C12 A10-B2-C12 A41-B3-C11 A31-B4-C11 A21-B1-C12 A11-B2-C12 A42-B3-C11 A32-B4-C11 A22-B1-C12 A12-B2-C12 A43-B3-C11 A33-B4-C11 A23-B1-C12 A13-B2-C12 A44-B3-C11 A34-B4-C11 A24-B1-C12 A14-B2-C12 A45-B3-C11 A35-B4-C11 A25-B1-C12 A15-B2-C12 A46-B3-C11 A36-B4-C11 A26-B1-C12 A16-B2-C12 A47-B3-C11 A37-B4-C11 A27-B1-C12 A17-B2-C12 A48-B3-C11 A38-B4-C11 A28-B1-C12 A18-B2-C12 A49-B3-C11 A39-B4-C11 A29-B1-C12 A19-B2-C12 A50-B3-C11 A40-B4-C11 A30-B1-C12 A20-B2-C12 A51-B3-C11 A41-B4-C11 A31-B1-C12 A21-B2-C12 A52-B3-C11 A42-B4-C11 A32-B1-C12 A22-B2-C12 A53-B3-C11 A43-B4-C11 A33-B1-C12 A23-B2-C12 A54-B3-C11 A44-B4-C11 A34-B1-C12 A24-B2-C12 A55-B3-C11 A45-B4-C11 A35-B1-C12 A25-B2-C12 A56-B3-C11 A46-B4-C11 A36-B1-C12 A26-B2-C12 A57-B3-C11 A47-B4-C11 A37-B1-C12 A27-B2-C12 A58-B3-C11 A48-B4-C11 A38-B1-C12 A28-B2-C12 A59-B3-C11 A49-B4-C11 A39-B1-C12 A29-B2-C12 A60-B3-C11 A50-B4-C11 A40-B1-C12 A30-B2-C12 A61-B3-C11 A51-B4-C11 A41-B1-C12 A31-B2-C12 A62-B3-C11 A52-B4-C11 A42-B1-C12 A32-B2-C12 A63-B3-C11 A53-B4-C11 A43-B1-C12 A33-B2-C12 A64-B3-C11 A54-B4-C11 A44-B1-C12 A34-B2-C12 A65-B3-C11 A55-B4-C11 A45-B1-C12 A35-B2-C12 A66-B3-C11 A56-B4-C11 A46-B1-C12 A36-B2-C12 A67-B3-C11 A57-B4-C11 A47-B1-C12 A37-B2-C12 A68-B3-C11 A58-B4-C11 A48-B1-C12 A38-B2-C12 A69-B3-C11 A59-B4-C11 A49-B1-C12 A39-B2-C12 A70-B3-C11 A60-B4-C11 A50-B1-C12 A40-B2-C12 A71-B3-C11 A61-B4-C11 A51-B1-C12 A41-B2-C12 A72-B3-C11 A62-B4-C11 A52-B1-C12 A42-B2-C12 A73-B3-C11 A63-B4-C11 A53-B1-C12 A43-B2-C12 A74-B3-C11 A64-B4-C11 A54-B1-C12 A44-B2-C12 A75-B3-C11 A65-B4-C11 A55-B1-C12 A45-B2-C12 A76-B3-C11 A66-B4-C11 A56-B1-C12 A46-B2-C12 A77-B3-C11 A67-B4-C11 A57-B1-C12 A47-B2-C12  A1-B4-C11 A68-B4-C11 A58-B1-C12 A48-B2-C12  A2-B4-C11 A69-B4-C11 A59-B1-C12 A49-B2-C12  A3-B4-C11 A70-B4-C11 A60-B1-C12 A50-B2-C12  A4-B4-C11 A71-B4-C11 A61-B1-C12 A51-B2-C12  A5-B4-C11 A72-B4-C11 A62-B1-C12 A52-B2-C12  A6-B4-C11 A73-B4-C11 A63-B1-C12 A53-B2-C12  A7-B4-C11 A74-B4-C11 A64-B1-C12 A54-B2-C12  A8-B4-C11 A75-B4-C11 A65-B1-C12 A55-B2-C12  A9-B4-C11 A76-B4-C11 A66-B1-C12 A56-B2-C12 A10-B4-C11 A77-B4-C11 A67-B1-C12 A57-B2-C12 A11-B4-C11  A1-B1-C12 A68-B1-C12 A58-B2-C12 A12-B4-C11  A2-B1-C12 A69-B1-C12 A59-B2-C12 A13-B4-C11  A3-B1-C12 A70-B1-C12 A60-B2-C12 A14-B4-C11  A4-B1-C12 A71-B1-C12 A61-B2-C12 A15-B4-C11  A5-B1-C12 A72-B1-C12 A62-B2-C12 A16-B4-C11  A6-B1-C12 A73-B1-C12 A63-B2-C12 A64-B2-C12 A54-B3-C12 A44-B4-C12 A34-B1-C13 A65-B2-C12 A55-B3-C12 A45-B4-C12 A35-B1-C13 A66-B2-C12 A56-B3-C12 A46-B4-C12 A36-B1-C13 A67-B2-C12 A57-B3-C12 A47-B4-C12 A37-B1-C13 A68-B2-C12 A58-B3-C12 A48-B4-C12 A38-B1-C13 A69-B2-C12 A59-B3-C12 A49-B4-C12 A39-B1-C13 A70-B2-C12 A60-B3-C12 A50-B4-C12 A40-B1-C13 A71-B2-C12 A61-B3-C12 A51-B4-C12 A41-B1-C13 A72-B2-C12 A62-B3-C12 A52-B4-C12 A42-B1-C13 A73-B2-C12 A63-B3-C12 A53-B4-C12 A43-B1-C13 A74-B2-C12 A64-B3-C12 A54-B4-C12 A44-B1-C13 A75-B2-C12 A65-B3-C12 A55-B4-C12 A45-B1-C13 A76-B2-C12 A66-B3-C12 A56-B4-C12 A46-B1-C13 A77-B2-C12 A67-B3-C12 A57-B4-C12 A47-B1-C13  A1-B3-C12 A68-B3-C12 A58-B4-C12 A48-B1-C13  A2-B3-C12 A69-B3-C12 A59-B4-C12 A49-B1-C13  A3-B3-C12 A70-B3-C12 A60-B4-C12 A50-B1-C13  A4-B3-C12 A71-B3-C12 A61-B4-C12 A51-B1-C13  A5-B3-C12 A72-B3-C12 A62-B4-C12 A52-B1-C13  A6-B3-C12 A73-B3-C12 A63-B4-C12 A53-B1-C13  A7-B3-C12 A74-B3-C12 A64-B4-C12 A54-B1-C13  A8-B3-C12 A75-B3-C12 A65-B4-C12 A55-B1-C13  A9-B3-C12 A76-B3-C12 A66-B4-C12 A56-B1-C13 A10-B3-C12 A77-B3-C12 A67-B4-C12 A57-B1-C13 A11-B3-C12  A1-B4-C12 A68-B4-C12 A58-B1-C13 A12-B3-C12  A2-B4-C12 A69-B4-C12 A59-B1-C13 A13-B3-C12  A3-B4-C12 A70-B4-C12 A60-B1-C13 A14-B3-C12  A4-B4-C12 A71-B4-C12 A61-B1-C13 A15-B3-C12  A5-B4-C12 A72-B4-C12 A62-B1-C13 A16-B3-C12  A6-B4-C12 A73-B4-C12 A63-B1-C13 A17-B3-C12  A7-B4-C12 A74-B4-C12 A64-B1-C13 A18-B3-C12  A8-B4-C12 A75-B4-C12 A65-B1-C13 A19-B3-C12  A9-B4-C12 A76-B4-C12 A66-B1-C13 A20-B3-C12 A10-B4-C12 A77-B4-C12 A67-B1-C13 A21-B3-C12 A11-B4-C12  A1-B1-C13 A68-B1-C13 A22-B3-C12 A12-B4-C12  A2-B1-C13 A69-B1-C13 A23-B3-C12 A13-B4-C12  A3-B1-C13 A70-B1-C13 A24-B3-C12 A14-B4-C12 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A37-B4-C12 A27-B1-C13 A17-B2-C13 A48-B3-C12 A38-B4-C12 A28-B1-C13 A18-B2-C13 A49-B3-C12 A39-B4-C12 A29-B1-C13 A19-B2-C13 A50-B3-C12 A40-B4-C12 A30-B1-C13 A20-B2-C13 A51-B3-C12 A41-B4-C12 A31-B1-C13 A21-B2-C13 A52-B3-C12 A42-B4-C12 A32-B1-C13 A22-B2-C13 A53-B3-C12 A43-B4-C12 A33-B1-C13 A23-B2-C13 A24-B2-C13 A14-B3-C13  A4-B4-C13 A71-B4-C13 A25-B2-C13 A15-B3-C13  A5-B4-C13 A72-B4-C13 A26-B2-C13 A16-B3-C13  A6-B4-C13 A73-B4-C13 A27-B2-C13 A17-B3-C13  A7-B4-C13 A74-B4-C13 A28-B2-C13 A18-B3-C13  A8-B4-C13 A75-B4-C13 A29-B2-C13 A19-B3-C13  A9-B4-C13 A76-B4-C13 A30-B2-C13 A20-B3-C13 A10-B4-C13 A77-B4-C13 A31-B2-C13 A21-B3-C13 A11-B4-C13  A1-B1-C14 A32-B2-C13 A22-B3-C13 A12-B4-C13  A2-B1-C14 A33-B2-C13 A23-B3-C13 A13-B4-C13  A3-B1-C14 A34-B2-C13 A24-B3-C13 A14-B4-C13  A4-B1-C14 A35-B2-C13 A25-B3-C13 A15-B4-C13  A5-B1-C14 A36-B2-C13 A26-B3-C13 A16-B4-C13  A6-B1-C14 A37-B2-C13 A27-B3-C13 A17-B4-C13  A7-B1-C14 A38-B2-C13 A28-B3-C13 A18-B4-C13  A8-B1-C14 A39-B2-C13 A29-B3-C13 A19-B4-C13  A9-B1-C14 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A65-B4-C13 A55-B1-C14  A9-B3-C13 A76-B3-C13 A66-B4-C13 A56-B1-C14 A10-B3-C13 A77-B3-C13 A67-B4-C13 A57-B1-C14 A11-B3-C13  A1-B4-C13 A68-B4-C13 A58-B1-C14 A12-B3-C13  A2-B4-C13 A69-B4-C13 A59-B1-C14 A13-B3-C13  A3-B4-C13 A70-B4-C13 A60-B1-C14 A61-B1-C14 A51-B2-C14 A41-B3-C14 A31-B4-C14 A62-B1-C14 A52-B2-C14 A42-B3-C14 A32-B4-C14 A63-B1-C14 A53-B2-C14 A43-B3-C14 A33-B4-C14 A64-B1-C14 A54-B2-C14 A44-B3-C14 A34-B4-C14 A65-B1-C14 A55-B2-C14 A45-B3-C14 A35-B4-C14 A66-B1-C14 A56-B2-C14 A46-B3-C14 A36-B4-C14 A67-B1-C14 A57-B2-C14 A47-B3-C14 A37-B4-C14 A68-B1-C14 A58-B2-C14 A48-B3-C14 A38-B4-C14 A69-B1-C14 A59-B2-C14 A49-B3-C14 A39-B4-C14 A70-B1-C14 A60-B2-C14 A50-B3-C14 A40-B4-C14 A71-B1-C14 A61-B2-C14 A51-B3-C14 A41-B4-C14 A72-B1-C14 A62-B2-C14 A52-B3-C14 A42-B4-C14 A73-B1-C14 A63-B2-C14 A53-B3-C14 A43-B4-C14 A74-B1-C14 A64-B2-C14 A54-B3-C14 A44-B4-C14 A75-B1-C14 A65-B2-C14 A55-B3-C14 A45-B4-C14 A76-B1-C14 A66-B2-C14 A56-B3-C14 A46-B4-C14 A77-B1-C14 A67-B2-C14 A57-B3-C14 A47-B4-C14  A1-B2-C14 A68-B2-C14 A58-B3-C14 A48-B4-C14  A2-B2-C14 A69-B2-C14 A59-B3-C14 A49-B4-C14  A3-B2-C14 A70-B2-C14 A60-B3-C14 A50-B4-C14  A4-B2-C14 A71-B2-C14 A61-B3-C14 A51-B4-C14  A5-B2-C14 A72-B2-C14 A62-B3-C14 A52-B4-C14  A6-B2-C14 A73-B2-C14 A63-B3-C14 A53-B4-C14  A7-B2-C14 A74-B2-C14 A64-B3-C14 A54-B4-C14  A8-B2-C14 A75-B2-C14 A65-B3-C14 A55-B4-C14  A9-B2-C14 A76-B2-C14 A66-B3-C14 A56-B4-C14 A10-B2-C14 A77-B2-C14 A67-B3-C14 A57-B4-C14 A11-B2-C14  A1-B3-C14 A68-B3-C14 A58-B4-C14 A12-B2-C14  A2-B3-C14 A69-B3-C14 A59-B4-C14 A13-B2-C14  A3-B3-C14 A70-B3-C14 A60-B4-C14 A14-B2-C14  A4-B3-C14 A71-B3-C14 A61-B4-C14 A15-B2-C14  A5-B3-C14 A72-B3-C14 A62-B4-C14 A16-B2-C14  A6-B3-C14 A73-B3-C14 A63-B4-C14 A17-B2-C14  A7-B3-C14 A74-B3-C14 A64-B4-C14 A18-B2-C14  A8-B3-C14 A75-B3-C14 A65-B4-C14 A19-B2-C14  A9-B3-C14 A76-B3-C14 A66-B4-C14 A20-B2-C14 A10-B3-C14 A77-B3-C14 A67-B4-C14 A21-B2-C14 A11-B3-C14  A1-B4-C14 A68-B4-C14 A22-B2-C14 A12-B3-C14  A2-B4-C14 A69-B4-C14 A23-B2-C14 A13-B3-C14  A3-B4-C14 A70-B4-C14 A24-B2-C14 A14-B3-C14  A4-B4-C14 A71-B4-C14 A25-B2-C14 A15-B3-C14  A5-B4-C14 A72-B4-C14 A26-B2-C14 A16-B3-C14  A6-B4-C14 A73-B4-C14 A27-B2-C14 A17-B3-C14  A7-B4-C14 A74-B4-C14 A28-B2-C14 A18-B3-C14  A8-B4-C14 A75-B4-C14 A29-B2-C14 A19-B3-C14  A9-B4-C14 A76-B4-C14 A30-B2-C14 A20-B3-C14 A10-B4-C14 A77-B4-C14 A31-B2-C14 A21-B3-C14 A11-B4-C14  A1-B1-C15 A32-B2-C14 A22-B3-C14 A12-B4-C14  A2-B1-C15 A33-B2-C14 A23-B3-C14 A13-B4-C14  A3-B1-C15 A34-B2-C14 A24-B3-C14 A14-B4-C14  A4-B1-C15 A35-B2-C14 A25-B3-C14 A15-B4-C14  A5-B1-C15 A36-B2-C14 A26-B3-C14 A16-B4-C14  A6-B1-C15 A37-B2-C14 A27-B3-C14 A17-B4-C14  A7-B1-C15 A38-B2-C14 A28-B3-C14 A18-B4-C14  A8-B1-C15 A39-B2-C14 A29-B3-C14 A19-B4-C14  A9-B1-C15 A40-B2-C14 A30-B3-C14 A20-B4-C14 A10-B1-C15 A41-B2-C14 A31-B3-C14 A21-B4-C14 A11-B1-C15 A42-B2-C14 A32-B3-C14 A22-B4-C14 A12-B1-C15 A43-B2-C14 A33-B3-C14 A23-B4-C14 A13-B1-C15 A44-B2-C14 A34-B3-C14 A24-B4-C14 A14-B1-C15 A45-B2-C14 A35-B3-C14 A25-B4-C14 A15-B1-C15 A46-B2-C14 A36-B3-C14 A26-B4-C14 A16-B1-C15 A47-B2-C14 A37-B3-C14 A27-B4-C14 A17-B1-C15 A48-B2-C14 A38-B3-C14 A28-B4-C14 A18-B1-C15 A49-B2-C14 A39-B3-C14 A29-B4-C14 A19-B1-C15 A50-B2-C14 A40-B3-C14 A30-B4-C14 A20-B1-C15 A21-B1-C15 A11-B2-C15  A1-B3-C15 A68-B3-C15 A22-B1-C15 A12-B2-C15  A2-B3-C15 A69-B3-C15 A23-B1-C15 A13-B2-C15  A3-B3-C15 A70-B3-C15 A24-B1-C15 A14-B2-C15  A4-B3-C15 A71-B3-C15 A25-B1-C15 A15-B2-C15  A5-B3-C15 A72-B3-C15 A26-B1-C15 A16-B2-C15  A6-B3-C15 A73-B3-C15 A27-B1-C15 A17-B2-C15  A7-B3-C15 A74-B3-C15 A28-B1-C15 A18-B2-C15  A8-B3-C15 A75-B3-C15 A29-B1-C15 A19-B2-C15  A9-B3-C15 A76-B3-C15 A30-B1-C15 A20-B2-C15 A10-B3-C15 A77-B3-C15 A31-B1-C15 A21-B2-C15 A11-B3-C15  A1-B4-C15 A32-B1-C15 A22-B2-C15 A12-B3-C15  A2-B4-C15 A33-B1-C15 A23-B2-C15 A13-B3-C15  A3-B4-C15 A34-B1-C15 A24-B2-C15 A14-B3-C15  A4-B4-C15 A35-B1-C15 A25-B2-C15 A15-B3-C15  A5-B4-C15 A36-B1-C15 A26-B2-C15 A16-B3-C15  A6-B4-C15 A37-B1-C15 A27-B2-C15 A17-B3-C15  A7-B4-C15 A38-B1-C15 A28-B2-C15 A18-B3-C15  A8-B4-C15 A39-B1-C15 A29-B2-C15 A19-B3-C15  A9-B4-C15 A40-B1-C15 A30-B2-C15 A20-B3-C15 A10-B4-C15 A41-B1-C15 A31-B2-C15 A21-B3-C15 A11-B4-C15 A42-B1-C15 A32-B2-C15 A22-B3-C15 A12-B4-C15 A43-B1-C15 A33-B2-C15 A23-B3-C15 A13-B4-C15 A44-B1-C15 A34-B2-C15 A24-B3-C15 A14-B4-C15 A45-B1-C15 A35-B2-C15 A25-B3-C15 A15-B4-C15 A46-B1-C15 A36-B2-C15 A26-B3-C15 A16-B4-C15 A47-B1-C15 A37-B2-C15 A27-B3-C15 A17-B4-C15 A48-B1-C15 A38-B2-C15 A28-B3-C15 A18-B4-C15 A49-B1-C15 A39-B2-C15 A29-B3-C15 A19-B4-C15 A50-B1-C15 A40-B2-C15 A30-B3-C15 A20-B4-C15 A51-B1-C15 A41-B2-C15 A31-B3-C15 A21-B4-C15 A52-B1-C15 A42-B2-C15 A32-B3-C15 A22-B4-C15 A53-B1-C15 A43-B2-C15 A33-B3-C15 A23-B4-C15 A54-B1-C15 A44-B2-C15 A34-B3-C15 A24-B4-C15 A55-B1-C15 A45-B2-C15 A35-B3-C15 A25-B4-C15 A56-B1-C15 A46-B2-C15 A36-B3-C15 A26-B4-C15 A57-B1-C15 A47-B2-C15 A37-B3-C15 A27-B4-C15 A58-B1-C15 A48-B2-C15 A38-B3-C15 A28-B4-C15 A59-B1-C15 A49-B2-C15 A39-B3-C15 A29-B4-C15 A60-B1-C15 A50-B2-C15 A40-B3-C15 A30-B4-C15 A61-B1-C15 A51-B2-C15 A41-B3-C15 A31-B4-C15 A62-B1-C15 A52-B2-C15 A42-B3-C15 A32-B4-C15 A63-B1-C15 A53-B2-C15 A43-B3-C15 A33-B4-C15 A64-B1-C15 A54-B2-C15 A44-B3-C15 A34-B4-C15 A65-B1-C15 A55-B2-C15 A45-B3-C15 A35-B4-C15 A66-B1-C15 A56-B2-C15 A46-B3-C15 A36-B4-C15 A67-B1-C15 A57-B2-C15 A47-B3-C15 A37-B4-C15 A68-B1-C15 A58-B2-C15 A48-B3-C15 A38-B4-C15 A69-B1-C15 A59-B2-C15 A49-B3-C15 A39-B4-C15 A70-B1-C15 A60-B2-C15 A50-B3-C15 A40-B4-C15 A71-B1-C15 A61-B2-C15 A51-B3-C15 A41-B4-C15 A72-B1-C15 A62-B2-C15 A52-B3-C15 A42-B4-C15 A73-B1-C15 A63-B2-C15 A53-B3-C15 A43-B4-C15 A74-B1-C15 A64-B2-C15 A54-B3-C15 A44-B4-C15 A75-B1-C15 A65-B2-C15 A55-B3-C15 A45-B4-C15 A76-B1-C15 A66-B2-C15 A56-B3-C15 A46-B4-C15 A77-B1-C15 A67-B2-C15 A57-B3-C15 A47-B4-C15  A1-B2-C15 A68-B2-C15 A58-B3-C15 A48-B4-C15  A2-B2-C15 A69-B2-C15 A59-B3-C15 A49-B4-C15  A3-B2-C15 A70-B2-C15 A60-B3-C15 A50-B4-C15  A4-B2-C15 A71-B2-C15 A61-B3-C15 A51-B4-C15  A5-B2-C15 A72-B2-C15 A62-B3-C15 A52-B4-C15  A6-B2-C15 A73-B2-C15 A63-B3-C15 A53-B4-C15  A7-B2-C15 A74-B2-C15 A64-B3-C15 A54-B4-C15  A8-B2-C15 A75-B2-C15 A65-B3-C15 A55-B4-C15  A9-B2-C15 A76-B2-C15 A66-B3-C15 A56-B4-C15 A10-B2-C15 A77-B2-C15 A67-B3-C15 A57-B4-C15 A58-B4-C15 A48-B1-C16 A38-B2-C16 A28-B3-C16 A59-B4-C15 A49-B1-C16 A39-B2-C16 A29-B3-C16 A60-B4-C15 A50-B1-C16 A40-B2-C16 A30-B3-C16 A61-B4-C15 A51-B1-C16 A41-B2-C16 A31-B3-C16 A62-B4-C15 A52-B1-C16 A42-B2-C16 A32-B3-C16 A63-B4-C15 A53-B1-C16 A43-B2-C16 A33-B3-C16 A64-B4-C15 A54-B1-C16 A44-B2-C16 A34-B3-C16 A65-B4-C15 A55-B1-C16 A45-B2-C16 A35-B3-C16 A66-B4-C15 A56-B1-C16 A46-B2-C16 A36-B3-C16 A67-B4-C15 A57-B1-C16 A47-B2-C16 A37-B3-C16 A68-B4-C15 A58-B1-C16 A48-B2-C16 A38-B3-C16 A69-B4-C15 A59-B1-C16 A49-B2-C16 A39-B3-C16 A70-B4-C15 A60-B1-C16 A50-B2-C16 A40-B3-C16 A71-B4-C15 A61-B1-C16 A51-B2-C16 A41-B3-C16 A72-B4-C15 A62-B1-C16 A52-B2-C16 A42-B3-C16 A73-B4-C15 A63-B1-C16 A53-B2-C16 A43-B3-C16 A74-B4-C15 A64-B1-C16 A54-B2-C16 A44-B3-C16 A75-B4-C15 A65-B1-C16 A55-B2-C16 A45-B3-C16 A76-B4-C15 A66-B1-C16 A56-B2-C16 A46-B3-C16 A77-B4-C15 A67-B1-C16 A57-B2-C16 A47-B3-C16  A1-B1-C16 A68-B1-C16 A58-B2-C16 A48-B3-C16  A2-B1-C16 A69-B1-C16 A59-B2-C16 A49-B3-C16  A3-B1-C16 A70-B1-C16 A60-B2-C16 A50-B3-C16  A4-B1-C16 A71-B1-C16 A61-B2-C16 A51-B3-C16  A5-B1-C16 A72-B1-C16 A62-B2-C16 A52-B3-C16  A6-B1-C16 A73-B1-C16 A63-B2-C16 A53-B3-C16  A7-B1-C16 A74-B1-C16 A64-B2-C16 A54-B3-C16  A8-B1-C16 A75-B1-C16 A65-B2-C16 A55-B3-C16  A9-B1-C16 A76-B1-C16 A66-B2-C16 A56-B3-C16 A10-B1-C16 A77-B1-C16 A67-B2-C16 A57-B3-C16 A11-B1-C16  A1-B2-C16 A68-B2-C16 A58-B3-C16 A12-B1-C16  A2-B2-C16 A69-B2-C16 A59-B3-C16 A13-B1-C16  A3-B2-C16 A70-B2-C16 A60-B3-C16 A14-B1-C16  A4-B2-C16 A71-B2-C16 A61-B3-C16 A15-B1-C16  A5-B2-C16 A72-B2-C16 A62-B3-C16 A16-B1-C16  A6-B2-C16 A73-B2-C16 A63-B3-C16 A17-B1-C16  A7-B2-C16 A74-B2-C16 A64-B3-C16 A18-B1-C16  A8-B2-C16 A75-B2-C16 A65-B3-C16 A19-B1-C16  A9-B2-C16 A76-B2-C16 A66-B3-C16 A20-B1-C16 A10-B2-C16 A77-B2-C16 A67-B3-C16 A21-B1-C16 A11-B2-C16  A1-B3-C16 A68-B3-C16 A22-B1-C16 A12-B2-C16  A2-B3-C16 A69-B3-C16 A23-B1-C16 A13-B2-C16  A3-B3-C16 A70-B3-C16 A24-B1-C16 A14-B2-C16  A4-B3-C16 A71-B3-C16 A25-B1-C16 A15-B2-C16  A5-B3-C16 A72-B3-C16 A26-B1-C16 A16-B2-C16  A6-B3-C16 A73-B3-C16 A27-B1-C16 A17-B2-C16  A7-B3-C16 A74-B3-C16 A28-B1-C16 A18-B2-C16  A8-B3-C16 A75-B3-C16 A29-B1-C16 A19-B2-C16  A9-B3-C16 A76-B3-C16 A30-B1-C16 A20-B2-C16 A10-B3-C16 A77-B3-C16 A31-B1-C16 A21-B2-C16 A11-B3-C16  A1-B4-C16 A32-B1-C16 A22-B2-C16 A12-B3-C16  A2-B4-C16 A33-B1-C16 A23-B2-C16 A13-B3-C16  A3-B4-C16 A34-B1-C16 A24-B2-C16 A14-B3-C16  A4-B4-C16 A35-B1-C16 A25-B2-C16 A15-B3-C16  A5-B4-C16 A36-B1-C16 A26-B2-C16 A16-B3-C16  A6-B4-C16 A37-B1-C16 A27-B2-C16 A17-B3-C16  A7-B4-C16 A38-B1-C16 A28-B2-C16 A18-B3-C16  A8-B4-C16 A39-B1-C16 A29-B2-C16 A19-B3-C16  A9-B4-C16 A40-B1-C16 A30-B2-C16 A20-B3-C16 A10-B4-C16 A41-B1-C16 A31-B2-C16 A21-B3-C16 A11-B4-C16 A42-B1-C16 A32-B2-C16 A22-B3-C16 A12-B4-C16 A43-B1-C16 A33-B2-C16 A23-B3-C16 A13-B4-C16 A44-B1-C16 A34-B2-C16 A24-B3-C16 A14-B4-C16 A45-B1-C16 A35-B2-C16 A25-B3-C16 A15-B4-C16 A46-B1-C16 A36-B2-C16 A26-B3-C16 A16-B4-C16 A47-B1-C16 A37-B2-C16 A27-B3-C16 A17-B4-C16 A18-B4-C16  A8-B1-C17 A75-B1-C17 A65-B2-C17 A19-B4-C16  A9-B1-C17 A76-B1-C17 A66-B2-C17 A20-B4-C16 A10-B1-C17 A77-B1-C17 A67-B2-C17 A21-B4-C16 A11-B1-C17  A1-B2-C17 A68-B2-C17 A22-B4-C16 A12-B1-C17  A2-B2-C17 A69-B2-C17 A23-B4-C16 A13-B1-C17  A3-B2-C17 A70-B2-C17 A24-B4-C16 A14-B1-C17  A4-B2-C17 A71-B2-C17 A25-B4-C16 A15-B1-C17  A5-B2-C17 A72-B2-C17 A26-B4-C16 A16-B1-C17  A6-B2-C17 A73-B2-C17 A27-B4-C16 A17-B1-C17  A7-B2-C17 A74-B2-C17 A28-B4-C16 A18-B1-C17  A8-B2-C17 A75-B2-C17 A29-B4-C16 A19-B1-C17  A9-B2-C17 A76-B2-C17 A30-B4-C16 A20-B1-C17 A10-B2-C17 A77-B2-C17 A31-B4-C16 A21-B1-C17 A11-B2-C17  A1-B3-C17 A32-B4-C16 A22-B1-C17 A12-B2-C17  A2-B3-C17 A33-B4-C16 A23-B1-C17 A13-B2-C17  A3-B3-C17 A34-B4-C16 A24-B1-C17 A14-B2-C17  A4-B3-C17 A35-B4-C16 A25-B1-C17 A15-B2-C17  A5-B3-C17 A36-B4-C16 A26-B1-C17 A16-B2-C17  A6-B3-C17 A37-B4-C16 A27-B1-C17 A17-B2-C17  A7-B3-C17 A38-B4-C16 A28-B1-C17 A18-B2-C17  A8-B3-C17 A39-B4-C16 A29-B1-C17 A19-B2-C17  A9-B3-C17 A40-B4-C16 A30-B1-C17 A20-B2-C17 A10-B3-C17 A41-B4-C16 A31-B1-C17 A21-B2-C17 A11-B3-C17 A42-B4-C16 A32-B1-C17 A22-B2-C17 A12-B3-C17 A43-B4-C16 A33-B1-C17 A23-B2-C17 A13-B3-C17 A44-B4-C16 A34-B1-C17 A24-B2-C17 A14-B3-C17 A45-B4-C16 A35-B1-C17 A25-B2-C17 A15-B3-C17 A46-B4-C16 A36-B1-C17 A26-B2-C17 A16-B3-C17 A47-B4-C16 A37-B1-C17 A27-B2-C17 A17-B3-C17 A48-B4-C16 A38-B1-C17 A28-B2-C17 A18-B3-C17 A49-B4-C16 A39-B1-C17 A29-B2-C17 A19-B3-C17 A50-B4-C16 A40-B1-C17 A30-B2-C17 A20-B3-C17 A51-B4-C16 A41-B1-C17 A31-B2-C17 A21-B3-C17 A52-B4-C16 A42-B1-C17 A32-B2-C17 A22-B3-C17 A53-B4-C16 A43-B1-C17 A33-B2-C17 A23-B3-C17 A54-B4-C16 A44-B1-C17 A34-B2-C17 A24-B3-C17 A55-B4-C16 A45-B1-C17 A35-B2-C17 A25-B3-C17 A56-B4-C16 A46-B1-C17 A36-B2-C17 A26-B3-C17 A57-B4-C16 A47-B1-C17 A37-B2-C17 A27-B3-C17 A58-B4-C16 A48-B1-C17 A38-B2-C17 A28-B3-C17 A59-B4-C16 A49-B1-C17 A39-B2-C17 A29-B3-C17 A60-B4-C16 A50-B1-C17 A40-B2-C17 A30-B3-C17 A61-B4-C16 A51-B1-C17 A41-B2-C17 A31-B3-C17 A62-B4-C16 A52-B1-C17 A42-B2-C17 A32-B3-C17 A63-B4-C16 A53-B1-C17 A43-B2-C17 A33-B3-C17 A64-B4-C16 A54-B1-C17 A44-B2-C17 A34-B3-C17 A65-B4-C16 A55-B1-C17 A45-B2-C17 A35-B3-C17 A66-B4-C16 A56-B1-C17 A46-B2-C17 A36-B3-C17 A67-B4-C16 A57-B1-C17 A47-B2-C17 A37-B3-C17 A68-B4-C16 A58-B1-C17 A48-B2-C17 A38-B3-C17 A69-B4-C16 A59-B1-C17 A49-B2-C17 A39-B3-C17 A70-B4-C16 A60-B1-C17 A50-B2-C17 A40-B3-C17 A71-B4-C16 A61-B1-C17 A51-B2-C17 A41-B3-C17 A72-B4-C16 A62-B1-C17 A52-B2-C17 A42-B3-C17 A73-B4-C16 A63-B1-C17 A53-B2-C17 A43-B3-C17 A74-B4-C16 A64-B1-C17 A54-B2-C17 A44-B3-C17 A75-B4-C16 A65-B1-C17 A55-B2-C17 A45-B3-C17 A76-B4-C16 A66-B1-C17 A56-B2-C17 A46-B3-C17 A77-B4-C16 A67-B1-C17 A57-B2-C17 A47-B3-C17  A1-B1-C17 A68-B1-C17 A58-B2-C17 A48-B3-C17  A2-B1-C17 A69-B1-C17 A59-B2-C17 A49-B3-C17  A3-B1-C17 A70-B1-C17 A60-B2-C17 A50-B3-C17  A4-B1-C17 A71-B1-C17 A61-B2-C17 A51-B3-C17  A5-B1-C17 A72-B1-C17 A62-B2-C17 A52-B3-C17  A6-B1-C17 A73-B1-C17 A63-B2-C17 A53-B3-C17  A7-B1-C17 A74-B1-C17 A64-B2-C17 A54-B3-C17 A55-B3-C17 A45-B4-C17 A35-B1-C18 A25-B2-C18 A56-B3-C17 A46-B4-C17 A36-B1-C18 A26-B2-C18 A57-B3-C17 A47-B4-C17 A37-B1-C18 A27-B2-C18 A58-B3-C17 A48-B4-C17 A38-B1-C18 A28-B2-C18 A59-B3-C17 A49-B4-C17 A39-B1-C18 A29-B2-C18 A60-B3-C17 A50-B4-C17 A40-B1-C18 A30-B2-C18 A61-B3-C17 A51-B4-C17 A41-B1-C18 A31-B2-C18 A62-B3-C17 A52-B4-C17 A42-B1-C18 A32-B2-C18 A63-B3-C17 A53-B4-C17 A43-B1-C18 A33-B2-C18 A64-B3-C17 A54-B4-C17 A44-B1-C18 A34-B2-C18 A65-B3-C17 A55-B4-C17 A45-B1-C18 A35-B2-C18 A66-B3-C17 A56-B4-C17 A46-B1-C18 A36-B2-C18 A67-B3-C17 A57-B4-C17 A47-B1-C18 A37-B2-C18 A68-B3-C17 A58-B4-C17 A48-B1-C18 A38-B2-C18 A69-B3-C17 A59-B4-C17 A49-B1-C18 A39-B2-C18 A70-B3-C17 A60-B4-C17 A50-B1-C18 A40-B2-C18 A71-B3-C17 A61-B4-C17 A51-B1-C18 A41-B2-C18 A72-B3-C17 A62-B4-C17 A52-B1-C18 A42-B2-C18 A73-B3-C17 A63-B4-C17 A53-B1-C18 A43-B2-C18 A74-B3-C17 A64-B4-C17 A54-B1-C18 A44-B2-C18 A75-B3-C17 A65-B4-C17 A55-B1-C18 A45-B2-C18 A76-B3-C17 A66-B4-C17 A56-B1-C18 A46-B2-C18 A77-B3-C17 A67-B4-C17 A57-B1-C18 A47-B2-C18  A1-B4-C17 A68-B4-C17 A58-B1-C18 A48-B2-C18  A2-B4-C17 A69-B4-C17 A59-B1-C18 A49-B2-C18  A3-B4-C17 A70-B4-C17 A60-B1-C18 A50-B2-C18  A4-B4-C17 A71-B4-C17 A61-B1-C18 A51-B2-C18  A5-B4-C17 A72-B4-C17 A62-B1-C18 A52-B2-C18  A6-B4-C17 A73-B4-C17 A63-B1-C18 A53-B2-C18  A7-B4-C17 A74-B4-C17 A64-B1-C18 A54-B2-C18  A8-B4-C17 A75-B4-C17 A65-B1-C18 A55-B2-C18  A9-B4-C17 A76-B4-C17 A66-B1-C18 A56-B2-C18 A10-B4-C17 A77-B4-C17 A67-B1-C18 A57-B2-C18 A11-B4-C17  A1-B1-C18 A68-B1-C18 A58-B2-C18 A12-B4-C17  A2-B1-C18 A69-B1-C18 A59-B2-C18 A13-B4-C17  A3-B1-C18 A70-B1-C18 A60-B2-C18 A14-B4-C17  A4-B1-C18 A71-B1-C18 A61-B2-C18 A15-B4-C17  A5-B1-C18 A72-B1-C18 A62-B2-C18 A16-B4-C17  A6-B1-C18 A73-B1-C18 A63-B2-C18 A17-B4-C17  A7-B1-C18 A74-B1-C18 A64-B2-C18 A18-B4-C17  A8-B1-C18 A75-B1-C18 A65-B2-C18 A19-B4-C17  A9-B1-C18 A76-B1-C18 A66-B2-C18 A20-B4-C17 A10-B1-C18 A77-B1-C18 A67-B2-C18 A21-B4-C17 A11-B1-C18  A1-B2-C18 A68-B2-C18 A22-B4-C17 A12-B1-C18  A2-B2-C18 A69-B2-C18 A23-B4-C17 A13-B1-C18  A3-B2-C18 A70-B2-C18 A24-B4-C17 A14-B1-C18  A4-B2-C18 A71-B2-C18 A25-B4-C17 A15-B1-C18  A5-B2-C18 A72-B2-C18 A26-B4-C17 A16-B1-C18  A6-B2-C18 A73-B2-C18 A27-B4-C17 A17-B1-C18  A7-B2-C18 A74-B2-C18 A28-B4-C17 A18-B1-C18  A8-B2-C18 A75-B2-C18 A29-B4-C17 A19-B1-C18  A9-B2-C18 A76-B2-C18 A30-B4-C17 A20-B1-C18 A10-B2-C18 A77-B2-C18 A31-B4-C17 A21-B1-C18 A11-B2-C18  A1-B3-C18 A32-B4-C17 A22-B1-C18 A12-B2-C18  A2-B3-C18 A33-B4-C17 A23-B1-C18 A13-B2-C18  A3-B3-C18 A34-B4-C17 A24-B1-C18 A14-B2-C18  A4-B3-C18 A35-B4-C17 A25-B1-C18 A15-B2-C18  A5-B3-C18 A36-B4-C17 A26-B1-C18 A16-B2-C18  A6-B3-C18 A37-B4-C17 A27-B1-C18 A17-B2-C18  A7-B3-C18 A38-B4-C17 A28-B1-C18 A18-B2-C18  A8-B3-C18 A39-B4-C17 A29-B1-C18 A19-B2-C1B  A9-B3-C18 A40-B4-C17 A30-B1-C18 A20-B2-C18 A10-B3-C18 A41-B4-C17 A31-B1-C18 A21-B2-C18 A11-B3-C18 A42-B4-C17 A32-B1-C18 A22-B2-C18 A12-B3-C18 A43-B4-C17 A33-B1-C18 A23-B2-C18 A13-B3-C18 A44-B4-C17 A34-B1-C18 A24-B2-C18 A14-B3-C18 A15-B3-C18  A5-B4-C18 A72-B4-C18 A62-B1-C19 A16-B3-C18  A6-B4-C18 A73-B4-C18 A63-B1-C19 A17-B3-C18  A7-B4-C18 A74-B4-C18 A64-B1-C19 A18-B3-C18  A8-B4-C18 A75-B4-C18 A65-B1-C19 A19-B3-C18  A9-B4-C18 A76-B4-C18 A66-B1-C19 A20-B3-C18 A10-B4-C18 A77-B4-C18 A67-B1-C19 A21-B3-C18 A11-B4-C18  A1-B1-C19 A68-B1-C19 A22-B3-C18 A12-B4-C18  A2-B1-C19 A69-B1-C19 A23-B3-C18 A13-B4-C18  A3-B1-C19 A70-B1-C19 A24-B3-C18 A14-B4-C18  A4-B1-C19 A71-B1-C19 A25-B3-C18 A15-B4-C18  A5-B1-C19 A72-B1-C19 A26-B3-C18 A16-B4-C18  A6-B1-C19 A73-B1-C19 A27-B3-C18 A17-B4-C18  A7-B1-C19 A74-B1-C19 A28-B3-C18 A18-B4-C18  A8-B1-C19 A75-B1-C19 A29-B3-C18 A19-B4-C18  A9-B1-C19 A76-B1-C19 A30-B3-C18 A20-B4-C18 A10-B1-C19 A77-B1-C19 A31-B3-C18 A21-B4-C18 A11-B1-C19  A1-B2-C19 A32-B3-C18 A22-B4-C18 A12-B1-C19  A2-B2-C19 A33-B3-C18 A23-B4-C18 A13-B1-C19  A3-B2-C19 A34-B3-C18 A24-B4-C18 A14-B1-C19  A4-B2-C19 A35-B3-C18 A25-B4-C18 A15-B1-C19  A5-B2-C19 A36-B3-C18 A26-B4-C18 A16-B1-C19  A6-B2-C19 A37-B3-C18 A27-B4-C18 A17-B1-C19  A7-B2-C19 A38-B3-C18 A28-B4-C18 A18-B1-C19  A8-B2-C19 A39-B3-C18 A29-B4-C18 A19-B1-C19  A9-B2-C19 A40-B3-C18 A30-B4-C18 A20-B1-C19 A10-B2-C19 A41-B3-C18 A31-B4-C18 A21-B1-C19 A11-B2-C19 A42-B3-C18 A32-B4-C18 A22-B1-C19 A12-B2-C19 A43-B3-C18 A33-B4-C18 A23-B1-C19 A13-B2-C19 A44-B3-C18 A34-B4-C18 A24-B1-C19 A14-B2-C19 A45-B3-C18 A35-B4-C18 A25-B1-C19 A15-B2-C19 A46-B3-C18 A36-B4-C18 A26-B1-C19 A16-B2-C19 A47-B3-C18 A37-B4-C18 A27-B1-C19 A17-B2-C19 A48-B3-C18 A38-B4-C18 A28-B1-C19 A18-B2-C19 A49-B3-C18 A39-B4-C18 A29-B1-C19 A19-B2-C19 A50-B3-C18 A40-B4-C18 A30-B1-C19 A20-B2-C19 A51-B3-C18 A41-B4-C18 A31-B1-C19 A21-B2-C19 A52-B3-C18 A42-B4-C18 A32-B1-C19 A22-B2-C19 A53-B3-C18 A43-B4-C18 A33-B1-C19 A23-B2-C19 A54-B3-C18 A44-B4-C18 A34-B1-C19 A24-B2-C19 A55-B3-C18 A45-B4-C18 A35-B1-C19 A25-B2-C19 A56-B3-C18 A46-B4-C18 A36-B1-C19 A26-B2-C19 A57-B3-C18 A47-B4-C18 A37-B1-C19 A27-B2-C19 A58-B3-C18 A48-B4-C18 A38-B1-C19 A28-B2-C19 A59-B3-C18 A49-B4-C18 A39-B1-C19 A29-B2-C19 A60-B3-C18 A50-B4-C18 A40-B1-C19 A30-B2-C19 A61-B3-C18 A51-B4-C18 A41-B1-C19 A31-B2-C19 A62-B3-C18 A52-B4-C18 A42-B1-C19 A32-B2-C19 A63-B3-C18 A53-B4-C18 A43-B1-C19 A33-B2-C19 A64-B3-C18 A54-B4-C18 A44-B1-C19 A34-B2-C19 A65-B3-C18 A55-B4-C18 A45-B1-C19 A35-B2-C19 A66-B3-C18 A56-B4-C18 A46-B1-C19 A36-B2-C19 A67-B3-C18 A57-B4-C18 A47-B1-C19 A37-B2-C19 A68-B3-C18 A58-B4-C18 A48-B1-C19 A38-B2-C19 A69-B3-C18 A59-B4-C18 A49-B1-C19 A39-B2-C19 A70-B3-C18 A60-B4-C18 A50-B1-C19 A40-B2-C19 A71-B3-C18 A61-B4-C18 A51-B1-C19 A41-B2-C19 A72-B3-C18 A62-B4-C18 A52-B1-C19 A42-B2-C19 A73-B3-C18 A63-B4-C18 A53-B1-C19 A43-B2-C19 A74-B3-C18 A64-B4-C18 A54-B1-C19 A44-B2-C19 A75-B3-C18 A65-B4-C18 A55-B1-C19 A45-B2-C19 A76-B3-C18 A66-B4-C18 A56-B1-C19 A46-B2-C19 A77-B3-C18 A67-B4-C18 A57-B1-C19 A47-B2-C19  A1-B4-C18 A68-B4-C18 A58-B1-C19 A48-B2-C19  A2-B4-C18 A69-B4-C18 A59-B1-C19 A49-B2-C19  A3-B4-C18 A70-B4-C18 A60-B1-C19 A50-B2-C19  A4-B4-C18 A71-B4-C18 A61-B1-C19 A51-B2-C19 A52-B2-C19 A42-B3-C19 A32-B4-C19 A22-B1-C20 A53-B2-C19 A43-B3-C19 A33-B4-C19 A23-B1-C20 A54-B2-C19 A44-B3-C19 A34-B4-C19 A24-B1-C20 A55-B2-C19 A45-B3-C19 A35-B4-C19 A25-B1-C20 A56-B2-C19 A46-B3-C19 A36-B4-C19 A26-B1-C20 A57-B2-C19 A47-B3-C19 A37-B4-C19 A27-B1-C20 A58-B2-C19 A48-B3-C19 A38-B4-C19 A28-B1-C20 A59-B2-C19 A49-B3-C19 A39-B4-C19 A29-B1-C20 A60-B2-C19 A50-B3-C19 A40-B4-C19 A30-B1-C20 A61-B2-C19 A51-B3-C19 A41-B4-C19 A31-B1-C20 A62-B2-C19 A52-B3-C19 A42-B4-C19 A32-B1-C20 A63-B2-C19 A53-B3-C19 A43-B4-C19 A33-B1-C20 A64-B2-C19 A54-B3-C19 A44-B4-C19 A34-B1-C20 A65-B2-C19 A55-B3-C19 A45-B4-C19 A35-B1-C20 A66-B2-C19 A56-B3-C19 A46-B4-C19 A36-B1-C20 A67-B2-C19 A57-B3-C19 A47-B4-C19 A37-B1-C20 A68-B2-C19 A58-B3-C19 A48-B4-C19 A38-B1-C20 A69-B2-C19 A59-B3-C19 A49-B4-C19 A39-B1-C20 A70-B2-C19 A60-B3-C19 A50-B4-C19 A40-B1-C20 A71-B2-C19 A61-B3-C19 A51-B4-C19 A41-B1-C20 A72-B2-C19 A62-B3-C19 A52-B4-C19 A42-B1-C20 A73-B2-C19 A63-B3-C19 A53-B4-C19 A43-B1-C20 A74-B2-C19 A64-B3-C19 A54-B4-C19 A44-B1-C20 A75-B2-C19 A65-B3-C19 A55-B4-C19 A45-B1-C20 A76-B2-C19 A66-B3-C19 A56-B4-C19 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A22-B2-C21 A12-B3-C21  A2-B4-C21 A69-B4-C21 A23-B2-C21 A13-B3-C21  A3-B4-C21 A70-B4-C21 A24-B2-C21 A14-B3-C21  A4-B4-C21 A71-B4-C21 A25-B2-C21 A15-B3-C21  A5-B4-C21 A72-B4-C21 A26-B2-C21 A16-B3-C21  A6-B4-C21 A73-B4-C21 A27-B2-C21 A17-B3-C21  A7-B4-C21 A74-B4-C21 A28-B2-C21 A18-B3-C21  A8-B4-C21 A75-B4-C21 A29-B2-C21 A19-B3-C21  A9-B4-C21 A76-B4-C21 A30-B2-C21 A20-B3-C21 A10-B4-C21 A77-B4-C21 A31-B2-C21 A21-B3-C21 A11-B4-C21  A1-B1-C22 A32-B2-C21 A22-B3-C21 A12-B4-C21  A2-B1-C22 A33-B2-C21 A23-B3-C21 A13-B4-C21  A3-B1-C22 A34-B2-C21 A24-B3-C21 A14-B4-C21  A4-B1-C22 A35-B2-C21 A25-B3-C21 A15-B4-C21  A5-B1-C22 A36-B2-C21 A26-B3-C21 A16-B4-C21  A6-B1-C22 A37-B2-C21 A27-B3-C21 A17-B4-C21  A7-B1-C22 A38-B2-C21 A28-B3-C21 A18-B4-C21  A8-B1-C22  A9-B1-C22 A76-B1-C22 A66-B2-C22 A56-B3-C22 A10-B1-C22 A77-B1-C22 A67-B2-C22 A57-B3-C22 A11-B1-C22  A1-B2-C22 A68-B2-C22 A58-B3-C22 A12-B1-C22  A2-B2-C22 A69-B2-C22 A59-B3-C22 A13-B1-C22  A3-B2-C22 A70-B2-C22 A60-B3-C22 A14-B1-C22  A4-B2-C22 A71-B2-C22 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A37-B4-C23 A27-B1-C24 A17-B2-C24  A7-B3-C24 A38-B4-C23 A28-B1-C24 A18-B2-C24  A8-B3-C24 A39-B4-C23 A29-B1-C24 A19-B2-C24  A9-B3-C24 A40-B4-C23 A30-B1-C24 A20-B2-C24 A10-B3-C24 A41-B4-C23 A31-B1-C24 A21-B2-C24 A11-B3-C24 A42-B4-C23 A32-B1-C24 A22-B2-C24 A12-B3-C24 A43-B4-C23 A33-B1-C24 A23-B2-C24 A13-B3-C24 A44-B4-C23 A34-B1-C24 A24-B2-C24 A14-B3-C24 A45-B4-C23 A35-B1-C24 A25-B2-C24 A15-B3-C24 A46-B4-C23 A36-B1-C24 A26-B2-C24 A16-B3-C24 A47-B4-C23 A37-B1-C24 A27-B2-C24 A17-B3-C24 A48-B4-C23 A38-B1-C24 A28-B2-C24 A18-B3-C24 A49-B4-C23 A39-B1-C24 A29-B2-C24 A19-B3-C24 A50-B4-C23 A40-B1-C24 A30-B2-C24 A20-B3-C24 A51-B4-C23 A41-B1-C24 A31-B2-C24 A21-B3-C24 A52-B4-C23 A42-B1-C24 A32-B2-C24 A22-B3-C24 A53-B4-C23 A43-B1-C24 A33-B2-C24 A23-B3-C24 A54-B4-C23 A44-B1-C24 A34-B2-C24 A24-B3-C24 A55-B4-C23 A45-B1-C24 A35-B2-C24 A25-B3-C24 A56-B4-C23 A46-B1-C24 A36-B2-C24 A26-B3-C24 A57-B4-C23 A47-B1-C24 A37-B2-C24 A27-B3-C24 A58-B4-C23 A48-B1-C24 A38-B2-C24 A28-B3-C24 A59-B4-C23 A49-B1-C24 A39-B2-C24 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A49-B4-C25 A39-B1-C26 A29-B2-C26 A60-B3-C25 A50-B4-C25 A40-B1-C26 A30-B2-C26 A61-B3-C25 A51-B4-C25 A41-B1-C26 A31-B2-C26 A62-B3-C25 A52-B4-C25 A42-B1-C26 A32-B2-C26 A63-B3-C25 A53-B4-C25 A43-B1-C26 A33-B2-C26 A64-B3-C25 A54-B4-C25 A44-B1-C26 A34-B2-C26 A65-B3-C25 A55-B4-C25 A45-B1-C26 A35-B2-C26 A66-B3-C25 A56-B4-C25 A46-B1-C26 A36-B2-C26 A67-B3-C25 A57-B4-C25 A47-B1-C26 A37-B2-C26 A68-B3-C25 A58-B4-C25 A48-B1-C26 A38-B2-C26 A69-B3-C25 A59-B4-C25 A49-B1-C26 A39-B2-C26 A40-B2-C26 A30-B3-C26 A20-B4-C26 A10-B1-C27 A41-B2-C26 A31-B3-C26 A21-B4-C26 A11-B1-C27 A42-B2-C26 A32-B3-C26 A22-B4-C26 A12-B1-C27 A43-B2-C26 A33-B3-C26 A23-B4-C26 A13-B1-C27 A44-B2-C26 A34-B3-C26 A24-B4-C26 A14-B1-C27 A45-B2-C26 A35-B3-C26 A25-B4-C26 A15-B1-C27 A46-B2-C26 A36-B3-C26 A26-B4-C26 A16-B1-C27 A47-B2-C26 A37-B3-C26 A27-B4-C26 A17-B1-C27 A48-B2-C26 A38-B3-C26 A28-B4-C26 A18-B1-C27 A49-B2-C26 A39-B3-C26 A29-B4-C26 A19-B1-C27 A50-B2-C26 A40-B3-C26 A30-B4-C26 A20-B1-C27 A51-B2-C26 A41-B3-C26 A31-B4-C26 A21-B1-C27 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A44-B1-C27 A75-B2-C26 A65-B3-C26 A55-B4-C26 A45-B1-C27 A76-B2-C26 A66-B3-C26 A56-B4-C26 A46-B1-C27 A77-B2-C26 A67-B3-C26 A57-B4-C26 A47-B1-C27  A1-B3-C26 A68-B3-C26 A58-B4-C26 A48-B1-C27  A2-B3-C26 A69-B3-C26 A59-B4-C26 A49-B1-C27  A3-B3-C26 A70-B3-C26 A60-B4-C26 A50-B1-C27  A4-B3-C26 A71-B3-C26 A61-B4-C26 A51-B1-C27  A5-B3-C26 A72-B3-C26 A62-B4-C26 A52-B1-C27  A6-B3-C26 A73-B3-C26 A63-B4-C26 A53-B1-C27  A7-B3-C26 A74-B3-C26 A64-B4-C26 A54-B1-C27  A8-B3-C26 A75-B3-C26 A65-B4-C26 A55-B1-C27  A9-B3-C26 A76-B3-C26 A66-B4-C26 A56-B1-C27 A10-B3-C26 A77-B3-C26 A67-B4-C26 A57-B1-C27 A11-B3-C26  A1-B4-C26 A68-B4-C26 A58-B1-C27 A12-B3-C26  A2-B4-C26 A69-B4-C26 A59-B1-C27 A13-B3-C26  A3-B4-C26 A70-B4-C26 A60-B1-C27 A14-B3-C26  A4-B4-C26 A71-B4-C26 A61-B1-C27 A15-B3-C26  A5-B4-C26 A72-B4-C26 A62-B1-C27 A16-B3-C26  A6-B4-C26 A73-B4-C26 A63-B1-C27 A17-B3-C26  A7-B4-C26 A74-B4-C26 A64-B1-C27 A18-B3-C26  A8-B4-C26 A75-B4-C26 A65-B1-C27 A19-B3-C26  A9-B4-C26 A76-B4-C26 A66-B1-C27 A20-B3-C26 A10-B4-C26 A77-B4-C26 A67-B1-C27 A21-B3-C26 A11-B4-C26  A1-B1-C27 A68-B1-C27 A22-B3-C26 A12-B4-C26  A2-B1-C27 A69-B1-C27 A23-B3-C26 A13-B4-C26  A3-B1-C27 A70-B1-C27 A24-B3-C26 A14-B4-C26  A4-B1-C27 A71-B1-C27 A25-B3-C26 A15-B4-C26  A5-B1-C27 A72-B1-C27 A26-B3-C26 A16-B4-C26  A6-B1-C27 A73-B1-C27 A27-B3-C26 A17-B4-C26  A7-B1-C27 A74-B1-C27 A28-B3-C26 A18-B4-C26  A8-B1-C27 A75-B1-C27 A29-B3-C26 A19-B4-C26  A9-B1-C27 A76-B1-C27 A77-B1-C27 A67-B2-C27 A57-B3-C27 A47-B4-C27  A1-B2-C27 A68-B2-C27 A58-B3-C27 A48-B4-C27  A2-B2-C27 A69-B2-C27 A59-B3-C27 A49-B4-C27  A3-B2-C27 A70-B2-C27 A60-B3-C27 A50-B4-C27  A4-B2-C27 A71-B2-C27 A61-B3-C27 A51-B4-C27  A5-B2-C27 A72-B2-C27 A62-B3-C27 A52-B4-C27  A6-B2-C27 A73-B2-C27 A63-B3-C27 A53-B4-C27  A7-B2-C27 A74-B2-C27 A64-B3-C27 A54-B4-C27  A8-B2-C27 A75-B2-C27 A65-B3-C27 A55-B4-C27  A9-B2-C27 A76-B2-C27 A66-B3-C27 A56-B4-C27 A10-B2-C27 A77-B2-C27 A67-B3-C27 A57-B4-C27 A11-B2-C27  A1-B3-C27 A68-B3-C27 A58-B4-C27 A12-B2-C27  A2-B3-C27 A69-B3-C27 A59-B4-C27 A13-B2-C27  A3-B3-C27 A70-B3-C27 A60-B4-C27 A14-B2-C27  A4-B3-C27 A71-B3-C27 A61-B4-C27 A15-B2-C27  A5-B3-C27 A72-B3-C27 A62-B4-C27 A16-B2-C27  A6-B3-C27 A73-B3-C27 A63-B4-C27 A17-B2-C27  A7-B3-C27 A74-B3-C27 A64-B4-C27 A18-B2-C27  A8-B3-C27 A75-B3-C27 A65-B4-C27 A19-B2-C27  A9-B3-C27 A76-B3-C27 A66-B4-C27 A20-B2-C27 A10-B3-C27 A77-B3-C27 A67-B4-C27 A21-B2-C27 A11-B3-C27  A1-B4-C27 A68-B4-C27 A22-B2-C27 A12-B3-C27  A2-B4-C27 A69-B4-C27 A23-B2-C27 A13-B3-C27  A3-B4-C27 A70-B4-C27 A24-B2-C27 A14-B3-C27  A4-B4-C27 A71-B4-C27 A25-B2-C27 A15-B3-C27  A5-B4-C27 A72-B4-C27 A26-B2-C27 A16-B3-C27  A6-B4-C27 A73-B4-C27 A27-B2-C27 A17-B3-C27  A7-B4-C27 A74-B4-C27 A28-B2-C27 A18-B3-C27  A8-B4-C27 A75-B4-C27 A29-B2-C27 A19-B3-C27  A9-B4-C27 A76-B4-C27 A30-B2-C27 A20-B3-C27 A10-B4-C27 A77-B4-C27 A31-B2-C27 A21-B3-C27 A11-B4-C27  A1-B1-C28 A32-B2-C27 A22-B3-C27 A12-B4-C27  A2-B1-C28 A33-B2-C27 A23-B3-C27 A13-B4-C27  A3-B1-C28 A34-B2-C27 A24-B3-C27 A14-B4-C27  A4-B1-C28 A35-B2-C27 A25-B3-C27 A15-B4-C27  A5-B1-C28 A36-B2-C27 A26-B3-C27 A16-B4-C27  A6-B1-C28 A37-B2-C27 A27-B3-C27 A17-B4-C27  A7-B1-C28 A38-B2-C27 A28-B3-C27 A18-B4-C27  A8-B1-C28 A39-B2-C27 A29-B3-C27 A19-B4-C27  A9-B1-C28 A40-B2-C27 A30-B3-C27 A20-B4-C27 A10-B1-C28 A41-B2-C27 A31-B3-C27 A21-B4-C27 A11-B1-C28 A42-B2-C27 A32-B3-C27 A22-B4-C27 A12-B1-C28 A43-B2-C27 A33-B3-C27 A23-B4-C27 A13-B1-C28 A44-B2-C27 A34-B3-C27 A24-B4-C27 A14-B1-C28 A45-B2-C27 A35-B3-C27 A25-B4-C27 A15-B1-C28 A46-B2-C27 A36-B3-C27 A26-B4-C27 A16-B1-C28 A47-B2-C27 A37-B3-C27 A27-B4-C27 A17-B1-C28 A48-B2-C27 A38-B3-C27 A28-B4-C27 A18-B1-C28 A49-B2-C27 A39-B3-C27 A29-B4-C27 A19-B1-C28 A50-B2-C27 A40-B3-C27 A30-B4-C27 A20-B1-C28 A51-B2-C27 A41-B3-C27 A31-B4-C27 A21-B1-C28 A52-B2-C27 A42-B3-C27 A32-B4-C27 A22-B1-C28 A53-B2-C27 A43-B3-C27 A33-B4-C27 A23-B1-C28 A54-B2-C27 A44-B3-C27 A34-B4-C27 A24-B1-C28 A55-B2-C27 A45-B3-C27 A35-B4-C27 A25-B1-C28 A56-B2-C27 A46-B3-C27 A36-B4-C27 A26-B1-C28 A57-B2-C27 A47-B3-C27 A37-B4-C27 A27-B1-C28 A58-B2-C27 A48-B3-C27 A38-B4-C27 A28-B1-C28 A59-B2-C27 A49-B3-C27 A39-B4-C27 A29-B1-C28 A60-B2-C27 A50-B3-C27 A40-B4-C27 A30-B1-C28 A61-B2-C27 A51-B3-C27 A41-B4-C27 A31-B1-C28 A62-B2-C27 A52-B3-C27 A42-B4-C27 A32-B1-C28 A63-B2-C27 A53-B3-C27 A43-B4-C27 A33-B1-C28 A64-B2-C27 A54-B3-C27 A44-B4-C27 A34-B1-C28 A65-B2-C27 A55-B3-C27 A45-B4-C27 A35-B1-C28 A66-B2-C27 A56-B3-C27 A46-B4-C27 A36-B1-C28 A37-B1-C28 A27-B2-C28 A17-B3-C28  A7-B4-C28 A38-B1-C28 A28-B2-C28 A18-B3-C28  A8-B4-C28 A39-B1-C28 A29-B2-C28 A19-B3-C28  A9-B4-C28 A40-B1-C28 A30-B2-C28 A20-B3-C28 A10-B4-C28 A41-B1-C28 A31-B2-C28 A21-B3-C28 A11-B4-C28 A42-B1-C28 A32-B2-C28 A22-B3-C28 A12-B4-C28 A43-B1-C28 A33-B2-C28 A23-B3-C28 A13-B4-C28 A44-B1-C28 A34-B2-C28 A24-B3-C28 A14-B4-C28 A45-B1-C28 A35-B2-C28 A25-B3-C28 A15-B4-C28 A46-B1-C28 A36-B2-C28 A26-B3-C28 A16-B4-C28 A47-B1-C28 A37-B2-C28 A27-B3-C28 A17-B4-C28 A48-B1-C28 A38-B2-C28 A28-B3-C28 A18-B4-C28 A49-B1-C28 A39-B2-C28 A29-B3-C28 A19-B4-C28 A50-B1-C28 A40-B2-C28 A30-B3-C28 A20-B4-C28 A51-B1-C28 A41-B2-C28 A31-B3-C28 A21-B4-C28 A52-B1-C28 A42-B2-C28 A32-B3-C28 A22-B4-C28 A53-B1-C28 A43-B2-C28 A33-B3-C28 A23-B4-C28 A54-B1-C28 A44-B2-C28 A34-B3-C28 A24-B4-C28 A55-B1-C28 A45-B2-C28 A35-B3-C28 A25-B4-C28 A56-B1-C28 A46-B2-C28 A36-B3-C28 A26-B4-C28 A57-B1-C28 A47-B2-C28 A37-B3-C28 A27-B4-C28 A58-B1-C28 A48-B2-C28 A38-B3-C28 A28-B4-C28 A59-B1-C28 A49-B2-C28 A39-B3-C28 A29-B4-C28 A60-B1-C28 A50-B2-C28 A40-B3-C28 A30-B4-C28 A61-B1-C28 A51-B2-C28 A41-B3-C28 A31-B4-C28 A62-B1-C28 A52-B2-C28 A42-B3-C28 A32-B4-C28 A63-B1-C28 A53-B2-C28 A43-B3-C28 A33-B4-C28 A64-B1-C28 A54-B2-C28 A44-B3-C28 A34-B4-C28 A65-B1-C28 A55-B2-C28 A45-B3-C28 A35-B4-C28 A66-B1-C28 A56-B2-C28 A46-B3-C28 A36-B4-C28 A67-B1-C28 A57-B2-C28 A47-B3-C28 A37-B4-C28 A68-B1-C28 A58-B2-C28 A48-B3-C28 A38-B4-C28 A69-B1-C28 A59-B2-C28 A49-B3-C28 A39-B4-C28 A70-B1-C28 A60-B2-C28 A50-B3-C28 A40-B4-C28 A71-B1-C28 A61-B2-C28 A51-B3-C28 A41-B4-C28 A72-B1-C28 A62-B2-C28 A52-B3-C28 A42-B4-C28 A73-B1-C28 A63-B2-C28 A53-B3-C28 A43-B4-C28 A74-B1-C28 A64-B2-C28 A54-B3-C28 A44-B4-C28 A75-B1-C28 A65-B2-C28 A55-B3-C28 A45-B4-C28 A76-B1-C28 A66-B2-C28 A56-B3-C28 A46-B4-C28 A77-B1-C28 A67-B2-C28 A57-B3-C28 A47-B4-C28  A1-B2-C28 A68-B2-C28 A58-B3-C28 A48-B4-C28  A2-B2-C28 A69-B2-C28 A59-B3-C28 A49-B4-C28  A3-B2-C28 A70-B2-C28 A60-B3-C28 A50-B4-C28  A4-B2-C28 A71-B2-C28 A61-B3-C28 A51-B4-C28  A5-B2-C28 A72-B2-C28 A62-B3-C28 A52-B4-C28  A6-B2-C28 A73-B2-C28 A63-B3-C28 A53-B4-C28  A7-B2-C28 A74-B2-C28 A64-B3-C28 A54-B4-C28  A8-B2-C28 A75-B2-C28 A65-B3-C28 A55-B4-C28  A9-B2-C28 A76-B2-C28 A66-B3-C28 A56-B4-C28 A10-B2-C28 A77-B2-C28 A67-B3-C28 A57-B4-C28 A11-B2-C28  A1-B3-C28 A68-B3-C28 A58-B4-C28 A12-B2-C28  A2-B3-C28 A69-B3-C28 A59-B4-C28 A13-B2-C28  A3-B3-C28 A70-B3-C28 A60-B4-C28 A14-B2-C28  A4-B3-C28 A71-B3-C28 A61-B4-C28 A15-B2-C28  A5-B3-C28 A72-B3-C28 A62-B4-C28 A16-B2-C28  A6-B3-C28 A73-B3-C28 A63-B4-C28 A17-B2-C28  A7-B3-C28 A74-B3-C28 A64-B4-C28 A18-B2-C28  A8-B3-C28 A75-B3-C28 A65-B4-C28 A19-B2-C28  A9-B3-C28 A76-B3-C28 A66-B4-C28 A20-B2-C28 A10-B3-C28 A77-B3-C28 A67-B4-C28 A21-B2-C28 A11-B3-C28  A1-B4-C28 A68-B4-C28 A22-B2-C28 A12-B3-C28  A2-B4-C28 A69-B4-C28 A23-B2-C28 A13-B3-C28  A3-B4-C28 A70-B4-C28 A24-B2-C28 A14-B3-C28  A4-B4-C28 A71-B4-C28 A25-B2-C28 A15-B3-C28  A5-B4-C28 A72-B4-C28 A26-B2-C28 A16-B3-C28  A6-B4-C28 A73-B4-C28 A74-B4-C28 A64-B1-C29 A54-B2-C29 A44-B3-C29 A75-B4-C28 A65-B1-C29 A55-B2-C29 A45-B3-C29 A76-B4-C28 A66-B1-C29 A56-B2-C29 A46-B3-C29 A77-B4-C28 A67-B1-C29 A57-B2-C29 A47-B3-C29  A1-B1-C29 A68-B1-C29 A58-B2-C29 A48-B3-C29  A2-B1-C29 A69-B1-C29 A59-B2-C29 A49-B3-C29  A3-B1-C29 A70-B1-C29 A60-B2-C29 A50-B3-C29  A4-B1-C29 A71-B1-C29 A61-B2-C29 A51-B3-C29  A5-B1-C29 A72-B1-C29 A62-B2-C29 A52-B3-C29  A6-B1-C29 A73-B1-C29 A63-B2-C29 A53-B3-C29  A7-B1-C29 A74-B1-C29 A64-B2-C29 A54-B3-C29  A8-B1-C29 A75-B1-C29 A65-B2-C29 A55-B3-C29  A9-B1-C29 A76-B1-C29 A66-B2-C29 A56-B3-C29 A10-B1-C29 A77-B1-C29 A67-B2-C29 A57-B3-C29 A11-B1-C29  A1-B2-C29 A68-B2-C29 A58-B3-C29 A12-B1-C29  A2-B2-C29 A69-B2-C29 A59-B3-C29 A13-B1-C29  A3-B2-C29 A70-B2-C29 A60-B3-C29 A14-B1-C29  A4-B2-C29 A71-B2-C29 A61-B3-C29 A15-B1-C29  A5-B2-C29 A72-B2-C29 A62-B3-C29 A16-B1-C29  A6-B2-C29 A73-B2-C29 A63-B3-C29 A17-B1-C29  A7-B2-C29 A74-B2-C29 A64-B3-C29 A18-B1-C29  A8-B2-C29 A75-B2-C29 A65-B3-C29 A19-B1-C29  A9-B2-C29 A76-B2-C29 A66-B3-C29 A20-B1-C29 A10-B2-C29 A77-B2-C29 A67-B3-C29 A21-B1-C29 A11-B2-C29  A1-B3-C29 A68-B3-C29 A22-B1-C29 A12-B2-C29  A2-B3-C29 A69-B3-C29 A23-B1-C29 A13-B2-C29  A3-B3-C29 A70-B3-C29 A24-B1-C29 A14-B2-C29  A4-B3-C29 A71-B3-C29 A25-B1-C29 A15-B2-C29  A5-B3-C29 A72-B3-C29 A26-B1-C29 A16-B2-C29  A6-B3-C29 A73-B3-C29 A27-B1-C29 A17-B2-C29  A7-B3-C29 A74-B3-C29 A28-B1-C29 A18-B2-C29  A8-B3-C29 A75-B3-C29 A29-B1-C29 A19-B2-C29  A9-B3-C29 A76-B3-C29 A30-B1-C29 A20-B2-C29 A10-B3-C29 A77-B3-C29 A31-B1-C29 A21-B2-C29 A11-B3-C29  A1-B4-C29 A32-B1-C29 A22-B2-C29 A12-B3-C29  A2-B4-C29 A33-B1-C29 A23-B2-C29 A13-B3-C29  A3-B4-C29 A34-B1-C29 A24-B2-C29 A14-B3-C29  A4-B4-C29 A35-B1-C29 A25-B2-C29 A15-B3-C29  A5-B4-C29 A36-B1-C29 A26-B2-C29 A16-B3-C29  A6-B4-C29 A37-B1-C29 A27-B2-C29 A17-B3-C29  A7-B4-C29 A38-B1-C29 A28-B2-C29 A18-B3-C29  A8-B4-C29 A39-B1-C29 A29-B2-C29 A19-B3-C29  A9-B4-C29 A40-B1-C29 A30-B2-C29 A20-B3-C29 A10-B4-C29 A41-B1-C29 A31-B2-C29 A21-B3-C29 A11-B4-C29 A42-B1-C29 A32-B2-C29 A22-B3-C29 A12-B4-C29 A43-B1-C29 A33-B2-C29 A23-B3-C29 A13-B4-C29 A44-B1-C29 A34-B2-C29 A24-B3-C29 A14-B4-C29 A45-B1-C29 A35-B2-C29 A25-B3-C29 A15-B4-C29 A46-B1-C29 A36-B2-C29 A26-B3-C29 A16-B4-C29 A47-B1-C29 A37-B2-C29 A27-B3-C29 A17-B4-C29 A48-B1-C29 A38-B2-C29 A28-B3-C29 A18-B4-C29 A49-B1-C29 A39-B2-C29 A29-B3-C29 A19-B4-C29 A50-B1-C29 A40-B2-C29 A30-B3-C29 A20-B4-C29 A51-B1-C29 A41-B2-C29 A31-B3-C29 A21-B4-C29 A52-B1-C29 A42-B2-C29 A32-B3-C29 A22-B4-C29 A53-B1-C29 A43-B2-C29 A33-B3-C29 A23-B4-C29 A54-B1-C29 A44-B2-C29 A34-B3-C29 A24-B4-C29 A55-B1-C29 A45-B2-C29 A35-B3-C29 A25-B4-C29 A56-B1-C29 A46-B2-C29 A36-B3-C29 A26-B4-C29 A57-B1-C29 A47-B2-C29 A37-B3-C29 A27-B4-C29 A58-B1-C29 A48-B2-C29 A38-B3-C29 A28-B4-C29 A59-B1-C29 A49-B2-C29 A39-B3-C29 A29-B4-C29 A60-B1-C29 A50-B2-C29 A40-B3-C29 A30-B4-C29 A61-B1-C29 A51-B2-C29 A41-B3-C29 A31-B4-C29 A62-B1-C29 A52-B2-C29 A42-B3-C29 A32-B4-C29 A63-B1-C29 A53-B2-C29 A43-B3-C29 A33-B4-C29 A34-B4-C29 A24-B1-C30 A14-B2-C30  A4-B3-C30 A35-B4-C29 A25-B1-C30 A15-B2-C30  A5-B3-C30 A36-B4-C29 A26-B1-C30 A16-B2-C30  A6-B3-C30 A37-B4-C29 A27-B1-C30 A17-B2-C30  A7-B3-C30 A38-B4-C29 A28-B1-C30 A18-B2-C30  A8-B3-C30 A39-B4-C29 A29-B1-C30 A19-B2-C30  A9-B3-C30 A40-B4-C29 A30-B1-C30 A20-B2-C30 A10-B3-C30 A41-B4-C29 A31-B1-C30 A21-B2-C30 A11-B3-C30 A42-B4-C29 A32-B1-C30 A22-B2-C30 A12-B3-C30 A43-B4-C29 A33-B1-C30 A23-B2-C30 A13-B3-C30 A44-B4-C29 A34-B1-C30 A24-B2-C30 A14-B3-C30 A45-B4-C29 A35-B1-C30 A25-B2-C30 A15-B3-C30 A46-B4-C29 A36-B1-C30 A26-B2-C30 A16-B3-C30 A47-B4-C29 A37-B1-C30 A27-B2-C30 A17-B3-C30 A48-B4-C29 A38-B1-C30 A28-B2-C30 A18-B3-C30 A49-B4-C29 A39-B1-C30 A29-B2-C30 A19-B3-C30 A50-B4-C29 A40-B1-C30 A30-B2-C30 A20-B3-C30 A51-B4-C29 A41-B1-C30 A31-B2-C30 A21-B3-C30 A52-B4-C29 A42-B1-C30 A32-B2-C30 A22-B3-C30 A53-B4-C29 A43-B1-C30 A33-B2-C30 A23-B3-C30 A54-B4-C29 A44-B1-C30 A34-B2-C30 A24-B3-C30 A55-B4-C29 A45-B1-C30 A35-B2-C30 A25-B3-C30 A56-B4-C29 A46-B1-C30 A36-B2-C30 A26-B3-C30 A57-B4-C29 A47-B1-C30 A37-B2-C30 A27-B3-C30 A58-B4-C29 A48-B1-C30 A38-B2-C30 A28-B3-C30 A59-B4-C29 A49-B1-C30 A39-B2-C30 A29-B3-C30 A60-B4-C29 A50-B1-C30 A40-B2-C30 A30-B3-C30 A61-B4-C29 A51-B1-C30 A41-B2-C30 A31-B3-C30 A62-B4-C29 A52-B1-C30 A42-B2-C30 A32-B3-C30 A63-B4-C29 A53-B1-C30 A43-B2-C30 A33-B3-C30 A64-B4-C29 A54-B1-C30 A44-B2-C30 A34-B3-C30 A65-B4-C29 A55-B1-C30 A45-B2-C30 A35-B3-C30 A66-B4-C29 A56-B1-C30 A46-B2-C30 A36-B3-C30 A67-B4-C29 A57-B1-C30 A47-B2-C30 A37-B3-C30 A68-B4-C29 A58-B1-C30 A48-B2-C30 A38-B3-C30 A69-B4-C29 A59-B1-C30 A49-B2-C30 A39-B3-C30 A70-B4-C29 A60-B1-C30 A50-B2-C30 A40-B3-C30 A71-B4-C29 A61-B1-C30 A51-B2-C30 A41-B3-C30 A72-B4-C29 A62-B1-C30 A52-B2-C30 A42-B3-C30 A73-B4-C29 A63-B1-C30 A53-B2-C30 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A76-B2-C30 A66-B3-C30 A20-B1-C30 A10-B2-C30 A77-B2-C30 A67-B3-C30 A21-B1-C30 A11-B2-C30  A1-B3-C30 A68-B3-C30 A22-B1-C30 A12-B2-C30  A2-B3-C30 A69-B3-C30 A23-B1-C30 A13-B2-C30  A3-B3-C30 A70-B3-C30 A71-B3-C30 A61-B4-C30 A51-B1-C31 A41-B2-C31 A72-B3-C30 A62-B4-C30 A52-B1-C31 A42-B2-C31 A73-B3-C30 A63-B4-C30 A53-B1-C31 A43-B2-C31 A74-B3-C30 A64-B4-C30 A54-B1-C31 A44-B2-C31 A75-B3-C30 A65-B4-C30 A55-B1-C31 A45-B2-C31 A76-B3-C30 A66-B4-C30 A56-B1-C31 A46-B2-C31 A77-B3-C30 A67-B4-C30 A57-B1-C31 A47-B2-C31  A1-B4-C30 A68-B4-C30 A58-B1-C31 A48-B2-C31  A2-B4-C30 A69-B4-C30 A59-B1-C31 A49-B2-C31  A3-B4-C30 A70-B4-C30 A60-B1-C31 A50-B2-C31  A4-B4-C30 A71-B4-C30 A61-B1-C31 A51-B2-C31  A5-B4-C30 A72-B4-C30 A62-B1-C31 A52-B2-C31  A6-B4-C30 A73-B4-C30 A63-B1-C31 A53-B2-C31  A7-B4-C30 A74-B4-C30 A64-B1-C31 A54-B2-C31  A8-B4-C30 A75-B4-C30 A65-B1-C31 A55-B2-C31  A9-B4-C30 A76-B4-C30 A66-B1-C31 A56-B2-C31 A10-B4-C30 A77-B4-C30 A67-B1-C31 A57-B2-C31 A11-B4-C30  A1-B1-C31 A68-B1-C31 A58-B2-C31 A12-B4-C30  A2-B1-C31 A69-B1-C31 A59-B2-C31 A13-B4-C30  A3-B1-C31 A70-B1-C31 A60-B2-C31 A14-B4-C30  A4-B1-C31 A71-B1-C31 A61-B2-C31 A15-B4-C30  A5-B1-C31 A72-B1-C31 A62-B2-C31 A16-B4-C30  A6-B1-C31 A73-B1-C31 A63-B2-C31 A17-B4-C30  A7-B1-C31 A74-B1-C31 A64-B2-C31 A18-B4-C30  A8-B1-C31 A75-B1-C31 A65-B2-C31 A19-B4-C30  A9-B1-C31 A76-B1-C31 A66-B2-C31 A20-B4-C30 A10-B1-C31 A77-B1-C31 A67-B2-C31 A21-B4-C30 A11-B1-C31  A1-B2-C31 A68-B2-C31 A22-B4-C30 A12-B1-C31  A2-B2-C31 A69-B2-C31 A23-B4-C30 A13-B1-C31  A3-B2-C31 A70-B2-C31 A24-B4-C30 A14-B1-C31  A4-B2-C31 A71-B2-C31 A25-B4-C30 A15-B1-C31  A5-B2-C31 A72-B2-C31 A26-B4-C30 A16-B1-C31  A6-B2-C31 A73-B2-C31 A27-B4-C30 A17-B1-C31  A7-B2-C31 A74-B2-C31 A28-B4-C30 A18-B1-C31  A8-B2-C31 A75-B2-C31 A29-B4-C30 A19-B1-C31  A9-B2-C31 A76-B2-C31 A30-B4-C30 A20-B1-C31 A10-B2-C31 A77-B2-C31 A31-B4-C30 A21-B1-C31 A11-B2-C31  A1-B3-C31 A32-B4-C30 A22-B1-C31 A12-B2-C31  A2-B3-C31 A33-B4-C30 A23-B1-C31 A13-B2-C31  A3-B3-C31 A34-B4-C30 A24-B1-C31 A14-B2-C31  A4-B3-C31 A35-B4-C30 A25-B1-C31 A15-B2-C31  A5-B3-C31 A36-B4-C30 A26-B1-C31 A16-B2-C31  A6-B3-C31 A37-B4-C30 A27-B1-C31 A17-B2-C31  A7-B3-C31 A38-B4-C30 A28-B1-C31 A18-B2-C31  A8-B3-C31 A39-B4-C30 A29-B1-C31 A19-B2-C31  A9-B3-C31 A40-B4-C30 A30-B1-C31 A20-B2-C31 A10-B3-C31 A41-B4-C30 A31-B1-C31 A21-B2-C31 A11-B3-C31 A42-B4-C30 A32-B1-C31 A22-B2-C31 A12-B3-C31 A43-B4-C30 A33-B1-C31 A23-B2-C31 A13-B3-C31 A44-B4-C30 A34-B1-C31 A24-B2-C31 A14-B3-C31 A45-B4-C30 A35-B1-C31 A25-B2-C31 A15-B3-C31 A46-B4-C30 A36-B1-C31 A26-B2-C31 A16-B3-C31 A47-B4-C30 A37-B1-C31 A27-B2-C31 A17-B3-C31 A48-B4-C30 A38-B1-C31 A28-B2-C31 A18-B3-C31 A49-B4-C30 A39-B1-C31 A29-B2-C31 A19-B3-C31 A50-B4-C30 A40-B1-C31 A30-B2-C31 A20-B3-C31 A51-B4-C30 A41-B1-C31 A31-B2-C31 A21-B3-C31 A52-B4-C30 A42-B1-C31 A32-B2-C31 A22-B3-C31 A53-B4-C30 A43-B1-C31 A33-B2-C31 A23-B3-C31 A54-B4-C30 A44-B1-C31 A34-B2-C31 A24-B3-C31 A55-B4-C30 A45-B1-C31 A35-B2-C31 A25-B3-C31 A56-B4-C30 A46-B1-C31 A36-B2-C31 A26-B3-C31 A57-B4-C30 A47-B1-C31 A37-B2-C31 A27-B3-C31 A58-B4-C30 A48-B1-C31 A38-B2-C31 A28-B3-C31 A59-B4-C30 A49-B1-C31 A39-B2-C31 A29-B3-C31 A60-B4-C30 A50-B1-C31 A40-B2-C31 A30-B3-C31 A31-B3-C31 A62-B3-C31 A16-B4-C31 A47-B4-C31 A32-B3-C31 A63-B3-C31 A17-B4-C31 A48-B4-C31 A33-B3-C31 A64-B3-C31 A18-B4-C31 A49-B4-C31 A34-B3-C31 A65-B3-c31 A19-B4-C31 A50-B4-C31 A35-B3-C31 A66-B3-C31 A20-B4-C31 A51-B4-C31 A36-B3-C31 A67-B3-C31 A21-B4-C31 A52-B4-C31 A37-B3-C31 A68-B3-C31 A22-B4-C31 A53-B4-C31 A38-B3-C31 A69-B3-C31 A23-B4-C31 A54-B4-C31 A39-B3-C31 A70-B3-C31 A24-B4-C31 A55-B4-C31 A40-B3-C31 A71-B3-C31 A25-B4-C31 A56-B4-C31 A41-B3-C31 A72-B3-C31 A26-B4-C31 A57-B4-C31 A42-B3-C31 A73-B3-C31 A27-B4-C31 A58-B4-C31 A43-B3-C31 A74-B3-C31 A28-B4-C31 A59-B4-C31 A44-B3-C31 A75-B3-C31 A29-B4-C31 A60-B4-C31 A45-B3-C31 A76-B3-C31 A30-B4-C31 A61-B4-C31 A46-B3-C31 A77-B3-C31 A31-B4-C31 A62-B4-C31 A47-B3-C31  A1-B4-C31 A32-B4-C31 A63-B4-C31 A48-B3-C31  A2-B4-C31 A33-B4-C31 A64-B4-C31 A49-B3-C31  A3-B4-C31 A34-B4-C31 A65-B4-C31 A50-B3-C31  A4-B4-C31 A35-B4-C31 A66-B4-C31 A51-B3-C31  A5-B4-C31 A36-B4-C31 A67-B4-C31 A52-B3-C31  A6-B4-C31 A37-B4-C31 A68-B4-C31 A53-B3-C31  A7-B4-C31 A38-B4-C31 A69-B4-C31 A54-B3-C31  A8-B4-C31 A39-B4-C31 A70-B4-C31 A55-B3-C31  A9-B4-C31 A40-B4-C31 A71-B4-C31 A56-B3-C31 A10-B4-C31 A41-B4-C31 A72-B4-C31 A57-B3-C31 A11-B4-C31 A42-B4-C31 A73-B4-C31 A58-B3-C31 A12-B4-C31 A43-B4-C31 A74-B4-C31 A59-B3-C31 A13-B4-C31 A44-B4-C31 A75-B4-C31 A60-B3-C31 A14-B4-C31 A45-B4-C31 A76-B4-C31 A61-B3-C31 A15-B4-C31 A46-B4-C31 A77-B4-C31

[0098] Thus, for example, in table 4 the compound denoted as A60-B1-C7 is the product of the combination of group A60 in Table 1 and B1 in Table 2 and C7 in Table 3, namely 1H-indole-5-carboxylic acid (1-{1-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-amide:

[0099] Further preferred are compounds selected from the group consisting of:

[0100] benzyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl 1-3-methyl-butyl)-carbamate (Compound 1);

[0101] benzyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}1-2-methyl-butyl)-carbamate (Compound 2);

[0102] tert-butyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-carbamate (Compound 3);

[0103] benzyl (1S-{1S-[(3-acetyl-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3methyl-butyl)-carbamate (Compound 4);

[0104] N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-2-methylbutyl}-4-methylpiperazine-1-carboxamide (Compound 5);

[0105] benzyl {1S-[2-(4-methoxyphenylsulfamoyl)-ethylcarbamoyl]-2-methyl-butyl}-carbamate (Compound 6);

[0106] (2-cyclohexyl-1S-{3-phenyl-1S-[(2-phenylaminoethylsulfamoyl)-methyl]-propylcarbamoyl}ethyl)-carbamic acid tert-butyl ester (Compound 7);

[0107] 4-dimethylamino-N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methylbutyl)-benzamide(Compound 8);

[0108] quinoline-6-carboxylic acid (1S-{1S-[(4-metboxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-amide (Compound 9);

[0109] morpholine-4-carboxylic acid (2-cyclohexyl-1S-{3-phenyl-1S-[(2-phenylamino-ethylsulfamoyl)methyl]-propylcarbamoyl}-ethyl)-amide (Compound 10);

[0110] 4-(2-dimethylaminothiazol-4-yl)-N-{1S-[2-(4-methoxyphenylsulfamoyl)-ethylcarbamoyl]-3-methyl-butyl }benzamide (Compound 11);

[0111] 2S-acetylamino-3-cyclohexyl-N-{1-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propyl}propionamide (Compound 12);

[0112] 2R-acetylamino-3-cyclohexyl-N-{1-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propyl}propionamide (Compound 13);

[0113] 2RS-acetylamino-3-cyclohexyl-N-{1-[(4-hydroxyphenylsulfamoyl)methyl]-3-phenyl-propyl}-propionamide (Compound 14);

[0114] benzyl [6-(4-methoxyphenylsulfamoyl)-5S-(4-methyl-2S-{4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzoylamino}pentanoylamino)hexyl]carbamate (Compound 15);

[0115] N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenylpropylcarbamoyl}-3-methyl-butyl)-4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzamide (Compound 16);

[0116] N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-nicotinamide (Compound 19);

[0117] N-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-3-methyl-butyl)-isonicotinamide (Compound 20);

[0118] N-{1-[1-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}-1H-indole-5-carboxamide (Compound 21);

[0119] tert-butyl [3-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-3-methyl-butylcarbamoyl)phenyl]-carbamate (Compound 22);

[0120] 3-amino-N-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-3-methyl-butyl)-benzamide (Compound 23);

[0121] N-(1S-{5-amino-1S-[(4-methoxyphenylsulfamoyl)methyl]pentylcarbamoyl}-3-methyl-butyl)-4-[2-(pyridin-3-ylamino)-thiazol-4-yl]-benzamide (Compound 24);

[0122] benzyl [1S-(1S-{[3-(1-hydroxyethyl)phenylsulfamoyl]methyl}-3-phenylpropyl-carbamoyl)-3-methylbutyl]-carbamate (Compound 26);

[0123] morpholine 4-carboxylic acid (1S-{5-amino-1S-[(4-methoxyphenylsulfamoyl)methyl]-pentylcarbamoyl}-pentylcarbamoyl}-2-phenylmethanesulfonylethyl)amide;

[0124] (5S-[2S-(morpholin-4-ylcarbonyl)amino]-3-phenylmethanesulfonylpropionylamino}-6-phenylsulfamoylhexyl)carbamic acid benzyl ester;

[0125] morpholine 4-carboxylic acid (1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenylpropylcarbamoyl}-2-phenylmethanesulfonylethyl)amide;

[0126] N-(1S-{1S-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-cyclohexyl)-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide; and

[0127] N-(1S-{1S-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-cyclohexyl)-4-(4-propylpiperazin-1-yl)-benzamide.

[0128] The names of these compounds were generated using Autonom Version 2.1 or 4.0.

GENERAL SYNTHESIS

[0129] Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.

[0130] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), or Bachem (Torrance, Calif.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4^(th) Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.

[0131] The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0132] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C. and most preferably at about room (or ambient) temperature, e.g., about 20° C.

[0133] Compounds of Formula I can be prepared by the procedure illustrated and described in Schemes 1 and 2 below:

[0134] Compounds of Formula I in which R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in the Summary of the Invention can be prepared by proceeding as in the following Scheme 1 below.

[0135] Compounds of Formula I can be prepared by condensing a compound of formula 4 with a compound of formula 5. The compound of formula 4 may be in a free base or an acid addition salt form, preferably an acid addition salt form (e.g. p-toluenesulfonic acid salt, or the like). Typically, the condensation reaction is carried out under nitrogen in the presence of a suitable condensing agent (e.g. isobutyl chloroformate, PyBOP, HATU, or the like), a non-nucleophilic base (e.g. 4-methylmorpholine, triethylamine, or the like) and a suitable solvent (e.g., THF, DMF, or the like), at −20 to 0° C., preferably at about −10° C., and requires 45 minutes to 12 hours to complete. A detailed description of the condensation reaction is found in the Examples, infra.

[0136] Compounds of formula 4 in which R³ is as defined in the Summary of the Invention for Formula I can be prepared as illustrated and described below.

[0137] Treatment of an N-protected alpha amino acid compound of formula 1 with a condensing agent (e.g., isobutyl chloroformate, or the like) in the presence of a suitable base (e.g., 4-methylmorpholine, or the like) in a suitable solvent (e.g., THF, etc.) at a temperature of about −10 to 10° C., preferably 0° C., for about 5 to 20 hours, followed by reaction of the resulting anhydride intermediate with a suitable reducing agent (e.g., sodium borohydride, and the like) provides a 2-N-protected aminoethanol intermediate of formula 1a. Compounds of formula 1 are commercially available or they can be prepared by methods well known in the art.

[0138] Treatment of la with an alkylsulfonyl halide (e.g., methanesulfonylchloride, or the like) in the presence of a suitable base (e.g., triethylamine, etc.) and in a suitable solvent (e.g., DCM, and the like) and at a temperature of about −10 to 10° C., preferably 0° C., for about 5 to 20 hours provides the corresponding alkylsulfonyloxy derivative. Treatment of the alkylsulfonyloxy derivative with an acylating agent (e.g., cesium thiolacetate, or the like) in a suitable solvent (e.g., DMF, and the like) and at a temperature of about 10 to 30° C., preferably 20° C., for about 5 to 20 hours provides a thioester which upon reaction with chlorine gas in a suitable solvent (e.g., DCM, and the like) at a temperature of about 10 to 30° C., preferably 20° C., for about 15 minutes to about 2 hours provides a compound of formula 2.

[0139] Compounds of formula 3 can be prepared by reacting a compound of formula 2 with an amine of the formula NHR¹R² and then removing the protecting group (PG) to yield a compound of formula 4. Typically, the reaction with the amine is carried out in the presence of a suitable solvent (e.g., DCM, or the like) and at a temperature of about −10 to 10° C., preferably 0° C., for about 5 to 20 hours. Deprotection can be effected by any means that removes the protecting group and gives the desired product in reasonable yield. For example, when the protecting group is t-butoxycarbonyl, deprotecting can be effected with a suitable anhydrous acid (e.g., anhydrous hydrogen chloride, anhydrous p-toluenesulfonic acid, or the like) at ambient temperature for about 12 to 24 hours.

[0140] Compounds of formula 5 are either commercially available or they can be prepared by methods well known in the art. For examples, t-BOC alanine, t-BOC-leucine, t-BOC-isoleucine are commercially available. Compounds of formula 5 where R⁶ is other groups within the scope of the invention sacan be readily prepared commercially available alpha amino acids by methods well known in the art. Some such methods are disclosed in U.S. Pat. No. 6,136,844 the disclosure of which is incorporated by reference in its entirety.

[0141] Compounds of Formula I in which R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in the Summary of the Invention can also be prepared from compounds of formula 6 as illustrated and described in Scheme 2 below.

[0142] Compounds of Formula I can also be prepared by deprotecting a compound of formula 6 and then treating the resulting free amine with an acid of formula R⁶OH or its acid derivative such as acid chloride. The compound of formula 6 may be in a free base or an acid addition salt form, preferably an acid addition salt form (e.g. p-toluenesulfonic acid salt, or the like).

[0143] Deprotection can be effected by any means that removes the protecting group and gives the desired product in reasonable yield. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (3rd Edition) 1999. For example, when the protecting group is BOC, deprotection can be effected by treating with anhydrous hydrogen chloride in a suitable solvent (e.g., dichloromethane, diethyl ether, dioxane, or the like), at 10 to 30° C., preferably at about 20° C., and requires about 5 to 10 hours to complete. A detailed description of the deprotection reaction is found in Example 5, infra.

[0144] The reaction conditions employed for the coupling of the free amine of compound 6 with R⁶OH depend on the nature of R⁶OH. For example, if an acid is used, then the reaction is carried out in the presence of a coupling agent such as PyBOP as described in Scheme 1 above. If an acid chloride is used then the reaction is carried out in the presence of a base such as triethylamine, pyridine, and the like and in a suitable organic solvent such as tetrahydrofuran, methylene chloride, and the like.

[0145] The reaction can be carried out at temperatures from about 10 to about 30° C., preferably at about 20° C., and requires 3 to 20 hours to complete. A detailed description of the step 2 reaction is found in the Examples, infra.

[0146] Additional Processes for Preparing Compounds of Formula I:

[0147] Compounds of Formula I in which R⁶ is hydrogen can be prepared by deacylating a compound of Formula I in which R⁶ is —X³X⁴R¹³. For example, deacylation of a compound of Formula I in which R⁵ is t-butyloxycarbonyl or benzyloxycarbonyl can be effected by treating with anhydrous hydrogen chloride or hydrogen bromide in a suitable solvent (e.g., DCM, dioxane, glacial acetic acid, or the like) at 10 to 30° C., preferable at about 20° C., for 5 to 20 hours. A detailed description of the reaction is found in the Examples, infra.

[0148] Compounds of Formula I can be further treated with a reducing agent (e.g., NaBH₄, LiALH₄, or the like), in the presence of a suitable solvent (e.g., tetrahydrofuran (THF), dimethylformamide (DMF) or the like), at 10 to 30° C., preferably at about 20° C., and requires 15 minutes to 2 hours to complete. A detailed description of the reduction reaction is found in the Examples, infra.

[0149] A compound of Formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of Formula I can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts of the starting materials or intermediates.

[0150] The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of Formula I in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, or the like). A compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, or the like).

[0151] The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at approximately 0° C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material.

[0152] Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g. sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80° C.

[0153] Prodrug derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art (e.g., for further details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters. No. 16, Vol. 4, pp. 1985-1990). For example, appropriate drugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like).

[0154] Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (3rd Edition) 1999.

[0155] Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, and the like) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

[0156] In Summary, the compounds of Formula I are made by a process which comprises:

[0157] (A) reacting a compound of formula 4:

[0158] with a compound of formula 5:

[0159] in which R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in the Summary of the Invention; or

[0160] (B) reacting a compound of formula 7:

[0161] with an acid compound of formula R⁶OH or an acid derivative thereof, wherein R¹, R², R³, R⁴, R⁵ and R⁶ are defined in the Summary of the Invention; and

[0162] (C) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;

[0163] (D) optionally converting a salt form of a compound of Formula I to non-salt form;

[0164] (E) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;

[0165] (F) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;

[0166] (G) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers;

[0167] (H) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative;

[0168] optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form; and

[0169] (J) optionally modifying any of the R¹, R², R³, R⁴, R⁵ and R⁶ groups.

Pharmacology and Utility

[0170] The compounds of the invention are cysteine protease inhibitors. In particular the compounds of the invention inhibit the activity of cathepsins B, L, K and/or S and, as such, are useful for treating diseases in which cathepsin B, L, K and/or S activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the invention are useful in treating tumor invasion and metastasis, in particular as anti-angiogenic agents, rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders. Furthermore, the compounds of the invention are useful in treating bone resorption disorders, e.g., osteoporosis. The compounds of the invention also are useful in treating autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis. The compounds of the invention also are useful in treating allergic disorders, including, but not limited to asthma; and allogeneic immune reponses, including, but not limited to, organ transplants or tissue grafts.

[0171] The cysteine protease inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Typically, the assay measures protease-induced hydrolysis of a peptide-based substrate. Details of assays for measuring protease inhibitory activity are set forth in Examples 9, 10, 11 and 12, infra.

Administration and Pharmaceutical Compositions

[0172] In general, compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I may range from 0.1 micrograms per kilogram body weight (μg/kg) per day to 10 milligram per kilogram body weight (mg/kg) per day, typically 1 μg/kg/day to 1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 10 μg/day to 100 mg/day, typically 0.1 mg/day to 10 mg/day. In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.

[0173] The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0174] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, or the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.

[0175] The amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of Formula I for treating a given disease will comprise from 0.01% w to 10% w, preferably 0.3% w to 1% w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical compositions is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of Formula I are described in Example 13.

[0176] The compounds of Formula I can be administered alone or in combination with other compounds of Formula I or in combination with one or more other active ingredient(s). For example, the compounds of Formula I can be administered in combination with a therapeutically active amount of a bisphosphonic acid or acid ester derivative or any pharmaceutically acceptable salt thereof. Suitable bisphosphonic acids and acid ester derivatives include compounds corresponding to the following formula:

[0177] wherein X⁷ is a bond or (C₁₋₇)alkylene, each R²⁷ independently is hydrogen or (C₁₋₃₀)alkyl, R²⁸ and R²⁹ are selected independently from a group consisting of hydrogen, halo, optionally substituted (C₁₋₃₀)alkyl, (C₃₋₃₀)cycloalkyl, hetero(C₅₋₃₀)cycloalkyl, optionally substituted (C₆₋₁₀)aryl, hetero(C₆₋₁₀)aryl, NR³⁰R³⁰, OR³⁰, SR³⁰, wherein each R³⁰ independently is hydrogen, (C₁₋₁₀)alkyl, (C₃₋₁₀)cycloalkyl, optionally substituted (C₆₋₁₀)aryl, provided that both R²⁸ and R²⁹ are not selected from hydrogen or hydroxy when X⁷ is a bond; or R²⁸ and R²⁹ taken together form (C₂₋₉)alkylene; wherein (C₃₋₁₀)cycloalkyl includes adamantyl and the like, hetero(C₅₋₁₀)cycloalkyl includes pyrrolidinyl and the like, (C₆₋₁₀)aryl includes phenyl and naphthyl, and hetero(C₆₋₁₀)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like.

[0178] Instances wherein R²⁸ and/or R²⁹ are substituted (C₁₋₃₀)alkyl may include, but are not limited to, (C₁₋₃₀)alkyl substituted by hetero(C₅₋₁₀)cycloalkyl, (C₆₋₁₀)aryl, hetero(C₆₋₁₀)aryl, NR³¹R³¹, OR³¹ and SR³¹ , wherein each R³¹ is independently hydrogen or (C₁₋₁₀)alkyl; wherein hetero(C₅₋₁₀)cycloalkyl includes pyrrolidinyl and the like, (C₆₋₁₀)aryl includes phenyl and naphthyl, and hetero(C₆₋₁₀)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like. Suitable optionally substituted aryl groups include, but are not limited to, halo-substituted phenyl.

[0179] A non-limiting class of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R²⁸ is selected from the group consisting of hydrogen, hydroxy or halo, and R²⁹ is selected from the group consisting of optionally substituted (C₁₋₃₀)alkyl, halo and SR³⁰, wherein R³⁰ is (C₁₋₁₀)alkyl or phenyl.

[0180] A non-limiting subclass of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R²⁸ is selected from the group consisting of hydrogen, hydroxy and chloro and R²⁹ is selected from the group consisting of optionally substituted (C₁₋₃₀)alkyl, chloro and chlorophenylthio.

[0181] A non-limiting example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I include that in which X⁷ is a bond, each R²⁷ is hydrogen, R²⁸ is hydroxy and R²⁹ is 3-aminopropyl, namely 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (aka alendronic acid), or the monosodium trihydrate salt thereof, namely 4-amino-1-hydroxybutylidene-1,1-bisphosphonate monosodium trihydrate (aka alendronate monosodium trihydrate), described in U.S. Pat. Nos. 4,922,007, to Kieczykowski et al., issued May 1, 1990; 5,019,651, to Kieczykowski et al., issued May 28, 1991; 5,510,517, to Dauer et al., issued Apr. 23, 1996; 5,648,491, to Dauer et al., issued Jul. 15, 1997, all of which patents are incorporated by reference herein in their entirety.

[0182] Further non-limiting examples of bisphosphonic acids suitable for administration in combination with compounds of Formula I include the following:

[0183] cycloheptylaminomethylene-1,1-bisphosphonic acid (aka cimadronic acid), described in U.S. Pat. No. 4,970,335, to Isomura et al., issued Nov. 13, 1990;

[0184] 1,1-dichloromethylene-1,1-diphosphonic acid (aka clodronic acid) and the disodium salt thereof, namely clodronate disodium, described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967);

[0185] 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid (aka EB-1053);

[0186] 1-hydroxyethylidene-1,1-diphosphonic acid (aka etidronic acid);

[0187] 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid (aka ibandronic acid), described in U.S. Pat. No. 4,927,814, issued May 22, 1990;

[0188] 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (aka neridronic acid);

[0189] 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid (aka olpadronic acid);

[0190] 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (aka pamidronic acid);

[0191] 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid (aka piridronic acid), described in U.S. Pat. No. 4,761,406;

[0192] 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid (aka risedronic acid);

[0193] 4-chlorophenylthiomethylenebisphosphonic acid (aka tiludronic acid), described in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24, 1989; and

[0194] 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (aka zoledronic acid); all of which patents and other documents referred to above are incorporated by reference herein in their entirety.

[0195] A non-limiting subclass of bisphosphonic acids suitable for administration in combination with compounds of Formula I include those selected from the group consisting of alendronic acid, cimadronic acid, clodronic acid, tiludronic acid, etidronic acid, ibandronic acid, risedronic acid, piridronic acid, pamidronic acid, zolendronic acid, pharmaceutically acceptable salts thereof, and mixtures thereof. A further example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I is alendronic acid or a pharmaceutically acceptable salt thereof, and mixtures thereof. A further non-limiting example is alendronate monosodium trihydrate.

[0196] Compounds of Formula I can be administered in combination with a therapeutically active amount of an estrogen receptor agonist. Non-limiting examples of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include naturally occurring estrogens such as estradiol, estrone and estroil, or synthetic estrogen receptor agonists such as [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-(2-piperidin-1-ylethoxy)phenyl]methanone (aka raloxifene) and {2-[4-(1,2-diphenylbut-1-enyl)-phenoxy]ethyl}dimethylamine (aka tamoxifen). A non-limiting subclass of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include estrogen receptor partial agonists (i.e., estrogen receptor agonists with mixed agonist/antagonist properties), sometimes referred to as estrogen receptor modulators. Estrogen receptor partial agonists can exert tissue-selective estrogen agonist effects. Tamoxifen, for example, selectively exerts an estrogen agonist effect on the bone, in humans. Additional suitable estrogen receptor partial agonists are described in Tissue-Selective Actions Of Estrogen Analogs, Bone Vol. 17, No. 4, October 1995, 181S-190S. Certain 3-[4-(2-phenylindol-1-ylmethyl)phenyl]acrylamides, described in U.S. Pat. No. 5,985,910 to Miller et al., Nov. 16, 1999; benzothiphene compounds, described in U.S. Pat. No. 5,985,897 to Meuhl et al., Nov. 16, 1999; naphthyl compounds, described in U.S. Pat. No. 5,952,350 to Cullinan et al., Sep. 14, 1999; substituted benzothiophene compounds, described in U.S. Pat. No. 5,962,475 to Schmid et al., Oct. 4, 1999, are suitable estrogen receptor partial agonists for administration with the compounds of Formula I; all of which patents and other documents referred to above are incorporated by reference herein in their entirety.

[0197] More particularly a pharmaceutical composition of this invention may comprise a therapeutically effect amount of a compound of Formula I in combination with one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effect amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effect amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipient(s). Non-limiting examples of such bisphosphonic acids include 1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid, 1-hydroxyethylidene-1,1-diphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid, 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof; particularly 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof and preferably 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.

EXAMPLES

[0198] The following preparations of intermediates (References) and compounds of Formula I (Examples) are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Reference 1 Synthesis of tert-butyl 1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamate, i.e., a compound of formula 3 in which PG is tert-butoxycarbonyl, R¹ is 4-methoxyphenyl and R³ is 2-phenylethyl

[0199]

[0200] A mixture of 1S-chlorosulfonylmethyl-3-phenylpropylcarbamate (0.96 g, 2.76 mmol) and 4-methoxyaniline (0.34 g, 2.76 mmol) in DCM (15 mL) was cooled to 0° C. and triethylamine (0.846 mL, 6.07 mmol) was added. The mixture was stirred at room temperature for approximately 12 hours and then diluted with DCM (30 mL). The dilution was washed with 1N hydrochloric acid (30 mL), saturated aqueous sodium bicarbonate (30 mL), dried over magnesium sulfate, filtered and concentrated to dryness to provide tert-butyl 1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamate (0.60 g, 50% yield). R_(f)0.4, 30% ethyl acetate/hexane. ¹H NMR (CDCl₃): 1.42 (9H, s); 1.75-1.85 (2H, m); 2.52-2.75 (2H,m); 3.08 (2H, m); 3.75 (3H, s); 4.05 (1H, m); 5.02 (1H, d, J=9 Hz); 6.75 (2H, d, J=8 Hz) 7.07-7.28 (8H, m*).

[0201] Proceeding as in Reference 1 and using appropriate starting materials provided the following compounds of Formula 3:

[0202] tert-butyl 1S-(4-hydroxyphenylsulfamoylmethyl)-3-phenylpropylcarbamate; R_(f)0.45 (10% methanol/DCM);

[0203] tert-butyl 1S-(3-acetylphenylsulfamoylmethyl)-3-phenylpropylcarbamate; R_(f)0.25 (30% ethyl acetate/hexane);

[0204] benzyl 5S-tert-butoxycarbonylamino-6-(4-methoxyphenylsulfamoyl)hexylcarbamate; MS: (M+1) 536; and

[0205] benzyl 2-(4-methoxyphenylsulfamoyl)ethylcarbamate; ¹H NMR (chloroform-d): 3.20 (2H, t, J=6 Hz); 3.67 (2H, q, J=6 Hz); 3.78 (3H, s); 5..08 (2H, s); 5.39 (1H, t, J=6 Hz); 6.76 (1H, s); 6.82 (2H, d, J=9 Hz); 7.17 (2H, d, J=9 Hz); 7.32 (5H, s).

Reference 2 Synthesis of 2S-amino-N-(4-methoxyphenyl)-4-phenylbutane-1-sulfonamide hydrochloride, i.e., a compound of formula 4 in which R¹ is 4-methoxyphenyl and R³ is phenethyl

[0206]

[0207] A solution comprised of crude tert-butyl 1-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamate (1.92 g, 4.42 mmol), prepared as in Reference 1, in DCM (10 mL) was treated with a 4M solution of hydrogen chloride in dioxane (11 mL). The mixture was stirred for 16 hours at room temperature and diluted with diethyl ether. A resulting precipitate was collected by filtration, washed several times with diethyl ether and hexane and pumped dry to provide 2S-amino-N-4-methoxyphenyl-4-phenylbutane-1-sulfonamide hydrochloride with quantitative mass recovery. ¹H NMR (DMSO): 2.05 (2H, m); 2.6-2.7 (2H, m); 3.4 (3H, m*); 3.72 (3H, s); 6.9 (2H, d, J=7 Hz); 7.25 (5H, m); 7.3 (2H, d, J=7 Hz); 8.5 (br. s); 10.0 (1H, s).

[0208] Proceeding as in Reference 2 provided the following compounds of Formula 4:

[0209] 2S-amino-N-(4-hydroxyphenyl)-4-phenylbutane-1-sulfonamide hydrochloride; ¹H NMR (DMSO): 2.09 (2H, m); 2.72 (2H, m*); 3.68 (1H, m); 3.91-3.94 (2H, 2×dd); 7.22 (7H, m*); 7.67 (2H, d, J=7 Hz); 8.64 (2H, d, J=7 Hz); 8.7 (m*); and

[0210] benzyl 5S-amino-6-(4-methoxyphenylsulfamoyl)hexylcarbamate hydrochloride.

Reference 3 Synthesis of N-(3-acetylphenyl)-2S-amino-4-phenylbutane-1-sulfonamide p-toluenesulfonate, ie., a compound of formula 4 in which R¹ is 3-acetylphenyl and R³ is 2-phenylethyl:

[0211]

[0212] A solution comprised of crude tert-butyl 1S-(3-acetylphenylsulfamoylmethyl)-3-phenylpropylcarbamate, prepared as in Reference 1, in DCM (3 mL) was treated with azeotropically dried anhydrous p-toluenesulfonic acid (1.3 g, 6.83 mmol) in ether (3 mL). The mixture was stirred at room temperature for approximately 12 hours, diluted with diethyl ether (100 mL), washed with diethyl ether (2×30 mL) and pumped dry to provide N-(3-acetylphenyl)-2S-amino-4-phenylbutane-1-sulfonamide-p-toluenesulfonate (1.59 g, 59% yield). ¹H NMR (DMSO-d⁶): 1.99 (2H, m*); 2.28 (3H, s); 2.56 (3H, s*); 2.61 (2H, m*); 3.42-3.54 (3H, m*); 7.09-7.77 (13H, m*); 8.01 (2H, br. s); 10.4 (1H, s). MS (M+1, free amine): 347.

Reference 4 Synthesis of 2-amino-N-(4-methoxyphenyl)ethanesulfonamide, i.e., a compound of formula 4 in which R¹ is 4-methoxyphenyl and R³ is hydrogen

[0213]

[0214] A solution comprised of benzyl 2-(4-methoxyphenylsulfamoyl)ethylcarbamate (2.78 g, 7.63 mmol), prepared as in Reference 1, in ethanol (20 mL) and cyclohexene (20 mL) was treated with 20% palladium hydroxide (0.95 g). The mixture was heated at reflux for 2 hours, cooled, and concentrated to dryness. The solid was triturated with ether, filtered and dried to provide 2-amino-N-(4-methoxyphenyl)ethanesulfonamide (1.08 grams, 61% yield). ¹H NMR (DMSO-d⁶): 2.86 (2H, t, J=6.4 Hz); 3.04 (2H, t, J=6.4 Hz); 3.72 (3H, s); 4.16 (2H, br. s); 6.87 (2H, d, J=9 Hz); 7.05 (2H, d, J=9 Hz).

Reference 5 Synthesis of tert-butyl 1S-chlorosulfonylmethyl-3-phenylpropylcarbamate, i.e., a compound of formula 2 in which R³ is phenethyl and PG is tert-butoxycarbonyl

[0215]

[0216] A solution comprised of 2S-tert-butoxycarbonylamino-4-phenylbutyric acid (20.27 g, 72.56 mmol) in THF (100 mL) was cooled to 0° C. and then 4-methylmorpholine (7.98 mL, 72.56 mmol) and isobutyl chloroformate (9.41 mL, 72.56 mmol) were added. The mixture was allowed to stand for 10 minutes and then filtered. The filter was washed through with THF (100 mL) and the combined filtrates were added, with rapid stirring, to a solution of sodium borohydride (5.45 g, 145.1 mmol) in water (200 mL) at 0° C. The mixture was stirred for 30 minutes and then diluted with saturated aqueous sodium bicarbonate (400 mL) and ethyl acetate (200 mL). The mixture was stirred vigorously for 20 minutes, separated, and the organic phase was washed with brine (100 mL). The solution was dried over magnesium sulfate, filtered, and evaporated to dryness to provide tert-butyl 1S-hydroxymethyl-3-phenylpropylcarbamate.

[0217] The tert-butyl 1S-hydroxymethyl-3-phenylpropylcarbamate was dissolved in DCM (200 mL). The solution was cooled to 0° C. and then triethylamine (27.31 mL, 195.9 mmol) was added. The mixture was stirred vigorously while methanesulfonyl chloride (13.48 mL, 174.1 mmol) was added over 5 minutes. The mixture was stirred for an additional 30 minutes and then diluted with water (200 mL). The dilution was stirred for an additional 30 minutes and then the organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness to provide tert-butyl 1S-methanesulfonyloxymethyl-3-phenylpropylcarbamate.

[0218] A solution of cesium thiolacetate was prepared by treating a solution of thiolacetic acid (10.36 mL, 145.1 mmol) in methanol (100 mL) with cesium carbonate (23.64 g, 72.56 mmol), concentrating the mixture and dissolving the residue in DMF (50 mL). The tert-butyl 1S-methanesulfonyloxymethyl-3-phenylpropylcarbamate was dissolved in DMF (50 mL) and added to the cesium thiolacetate solution. The mixture was stirred at room temperature for approximately 12 hours and diluted with water (500 mL) and then ethyl acetate (300 mL). The mixture was stirred vigorously for 20 minutes and the organic phase was separated, washed with IN hydrochloric acid (200 mL), saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL), dried over a mixture of magnesium sulfate and decolorizing charcoal, filtered, and concentrated to dryness to provide tert-butyl 1S-acetylsulfanylmethyl-3-phenylpropyl)carbamate.

[0219] The tert-butyl 1S-acetylsulfanylmethyl-3-phenylpropyl)carbamate (14.73 g, 45.54 mmol) was dissolved in a 1:1 mixture of DCM:water (500 mL). The biphasic mixture was stirred rapidly and cooled to 0° C. Chlorine gas was bubbled into the solution for approximately 30 minutes (to the saturation point). The organic layer was separated, dried over magnesium sulfate, filtered, concentrated and the residue was recrystallized from DCM/hexane to provide tert-butyl 1S-chlorosulfonylmethyl-3-phenylpropylcarbamate (9.80 g, 62% yield).

[0220] Proceeding as in Reference 5 and using appropriate starting materials provided the following compounds of Formula 2:

[0221] (2-chlorosulfonylethyl)-carbamic acid tert-butyl ester;

[0222] (5-tert-butoxycarbonylamino-6-chlorosulfonylhexyl)-carbamic acid benzyl ester; and

[0223] (5-amino-1-chlorosulfonylmethylpentyl)-carbamic acid tert-butyl ester.

Reference 6 Synthesis of 2S-amino-N-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropyl]-4-methyl-pentanamide hydrochloride, i.e., a compound of formula 6 in which R¹ is 4-methoxyphenyl, R³ is 2-phenethyl and R⁴ is 2-methylpropyl and R⁵ is hydrogen

[0224]

[0225] A solution of tert-butyl 1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropyl-carbamoyl]-3-methylbutylcarbamate (1.1 g, 2 mmol) in dichloromethane (5 mL) was treated with a 1M solution of hydrogen chloride in diethyl ether (20 mL), with stirring, at room temperature for 5 hours and then concentrated to provide 2S-amino-N-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropyl]-4-methylpentanamide hydrochloride (810 mg, 84% yield).

Example 1 Synthesis of benzyl 1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate

[0226]

[0227] A solution comprised of 2S-benzyloxycarbonylamino-4-methylpentanoic acid (0.25 g, 0.944 mmol) in THF (10 mL) was cooled to −10 ° C. and then 4-methylmorpholine (0.104 mL, 0.944 mmol) and isobutyl chloroformate (0.122 mL, 0.944 mmol) were added. The reaction mixture was allowed 5 minutes and then 2S-amino-N-(4-methoxyphenyl)-4-phenylbutane-1-sulfonamide hydrochloride (0.35 g, 0.944 mmol), prepared as in Reference 2, and 4-methylmorpholine (0.104 mL, 0.944 mmol) were added sequentially. The reaction mixture was stirred for 45 minutes and then ethyl acetate (50 mL) was added. The reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate and brine (10 mL each), dried over MgSO₄, filtered and concentrated. Product was purified from the residue on a silica gel column, mobile phase 30-50% ethyl acetate/hexane and crystallized from DCM/diethyl ether/hexane to provide benzyl 1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamate (0.172 g, 31% yield). ¹H NMR (CDCl₃): 0.91 (6H, 2×d*); 1.4-1.81 (4H, m*); 1.93 (1H, m); 2.55 (2H, m); 3.1-3.26 (2H, 2×dd); 3.74 (3H, s); 4.18 (1H, m); 4.22 (1H, m); 5.07 (2H, dd); 5.48 (1H, d, J=7 Hz); 6.76 (2H, d, J=9 Hz); 6.89 (1H, d); 7.04-7.28 (12H, m); 7.87 (1H, s). MS (M+1) 582.

[0228] Proceeding as in Example 1 provided the following compounds of Formula I:

[0229] benzyl 1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-2-methyl-butyl-carbamate (Compound 2); ¹H NMR (CDCl₃): 0.85 (3H, t, J=6.5 Hz); 0.91 (3H, d J=6.5 Hz); 1.12 (1H, m); 1.52 (1H, m); 1.8-2.05 (4H, m*); 2.55 (2H, m*); 3.18 (2H, m); 3.73 (3H, s); 4.03 (1H, m); 4.31 (1H, m); 5.09 (2H, dd); 5.31 (1H, br d); 6.76 (3H, d+m); 7.05-7.31 (12H, m); 7.62 (1H, s). MS (M+1): 582;

[0230] tert-butyl 1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methyl-butylcarbamate (Compound 3); ¹H NMR (CDCl₃): 0.85 (6H, 2×d*); 0.93 (1H, m*); 1.44 (9H, s); 1.37-1.62 (3H, m*). 2.07 (2H, m); 2.64 (2H, m); 3.62 (1H, dd, J=13.6, 3.7 Hz); 3.79 (3H, s); 3.91 (1H, dd*); 3.96 (1H, m*); 4.31 (1H, m); 4.81 (1H, m); 6.5 (1H, d, J=7.4 Hz); 7.1-7.26 (7H);

[0231] benzyl 1S-[1S-(3-acetylphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl-carbamate (Compound 4); R_(f) (TLC, 20% ethyl acetate/CH₂Cl₂): 0.65; ¹H NMR (CDCl₃); 0.93 (6H, 2×d, J=6 Hz); 1.52 (1H, m); 1.67 (2H, m); 1.83 (1H, m); 1.98 (1H, m); 2.54-2.59 (5H, s, m*); 3.14-3.37 (2H, 2×dd); 4.11 (1H, m); 4.25 (1H, m); 5.07-5.11 (3H, s, d*); 6.59 (1H, d, J=8.4 Hz); 7.04-7.38 (13 H); 7.69 (1H, d); 7.82 (1H, s); 8.14 (1H, s). MS (M+1): 594;

[0232] N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-2-methylbutyl}-4-methylpiperazine-1-carboxamide (Compound 5); ¹H NMR (CDCl₃): 0.9 (3H, t, J=6 Hz); 1.00 (3H, d, J=6 Hz); 1.19 (1H, m); 1.56 (1H, m); 1.85 (1H, m); 2.01 (2H, m); 2.30 (3H, s); 2.42 (4H, m); 2.56 (2H, m); 3.15-3.32 (2H, 2×dd); 3.43 (4H, m); 3.77 (3H, s); 4.07 (1H, t, J=6 Hz); 4.23 (1H, m); 4.89 (1H, br d); 6.78 (2H, d); 7.00 (1H, d); 7.05-7.25 (7H, m); 8.28 (1H, br s). MS (M⁺) 574; and

[0233] benzyl 1S-[2-(4-methoxyphenylsulfamoyl)ethylcarbamoyl]-2-methylbutylcarbamate (Compound 6); R_(f) (TLC: 50% ethyl acetate/CH₂Cl₂): 0.65; ¹H NMR (CDCl₃): 0.84-0.92 (6H, d, t*); 1.09 (1H, m); 1.46 (1H, m); 1.89 (1H, m); 3.22 (2H, m); 3.68 (2H, m*); 3.74 (3H, s); 4.01 (1H, t, J=6 Hz); 5.02 (2H, dd); 5.35 (1H, d, J=8 Hz); 6.85 (2H, d, J=7.5 Hz); 7.24 (2H, 7.5 Hz); 7.30 (6H, s, d*).

[0234] (2-cyclohexyl-1S-{3-phenyl-1S-[(2-phenylaminoethylsulfamoyl)-methyl]-propylcarbamoyl}ethyl)-carbamic acid tert-butyl ester (Compound 7);

Example 2 Synthesis of 4-dimethylamino-N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}benzamide

[0235]

[0236] A solution comprised of 2S-amino-N-(4-methoxyphenyl)-4-phenylbutane-1-sulfonamide hydrochloride (0.371 g, 1 mmol), prepared as in Reference 2,2S-(4-dimethylaminobenzoylamino)-4-methylpentanoic acid (0.278 g, 1 mmol) and PyBOP (0.52 g, 1 mmol) in DMF (10 mL) was treated with triethylamine (0.418 mL, 3 mmol). The mixture was stirred at room temperature for approximately 12 hours and then diluted with ethyl acetate (30 mL), washed with 1N hydrochloric acid (10 mL) and saturated aqueous sodium bicarbonate (10 mL), dried (MgSO₄), filtered and concentrated to dryness. The product was crystallized twice from DCM/diethyl ether/hexane to provide 4-dimethylamino-N-{1S-[1S-(4-methoxyphenyl-sulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}benzamide (50 mg, 8.4% yield) as a diastereomeric/rotameric mixture. ¹H NMR (CDCl₃): 0.85-1.1 (6H, 2×d, t); 1.25 (1H, m); 1.5-2.2 (5H, 5×m*); 2.56 (2H, m); 3.02 (6H, s); 3.04-3.19 (2H, m*); 3.72 (3H, 2×s) 4.2-4.44 (1H, m*); 4.45, 4.67 (1H total, 2×dd); 6.7 (4H, 2×d*); 7.06-7.24 (8H, m*); 7.69 (2H, d, J=8.7 Hz); 7.92, 8.0 (1H total, 2×s).

[0237] Proceeding as in Example 2 provide the following compounds of Formula I:

[0238] quinoline-6-carboxylic acid (1-{1-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methylbutyl)-amide (Compound 9);

[0239] morpholine-4-carboxylic acid (2-cyclohexyl-1S-{3-phenyl-1S-[(2-phenylamino-ethylsulfamoyl)methyl]-propylcarbamoyl}-ethyl)-amide (Compound 10);

[0240] 4-(2-dimethylaminothiazol-4-yl)-N-{1S-[2-(4-methoxyphenylsulfamoyl)-ethylcarbamoyl]-3-methyl-butyl}benzamide (Compound 11);

[0241] (S)-2-acetylamino-3-cyclohexyl-N-{1-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propyl}-propionamide (Compound 12);

[0242] (R)-2-acetylamino-3-cyclohexyl-N-{1-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propyl }-propionamide (Compound 13);

[0243] 2(RS)-acetylamino-3-cyclohexyl-N-{1-[(4-hydroxyphenylsulfamoyl)methyl]-3-phenyl-propyl}-propionamide (Compound 14).

Example 3 Synthesis of benzyl 6-(4-methoxyphenylsulfamoyl)-5S-{4-methyl-2S-[4-(2-pyridin-3-ylaminothiazol-4-yl)-benzoylamino]pentanoylamino}hexylcarbamate

[0244]

[0245] A solution comprised of benzyl 5S-amino-6-(4-methoxyphenylsulfamoyl)-hexylcarbamate hydrochloride (0.254 g, 0.539 mmol), prepared as in Reference 2,4-methyl-2S-[4-(2-pyridin-3-ylaminothiazol-4-yl)benzoylamino]pentanoic acid hydrochloride (0.232 g, 0.539 mmol) and PyBOP (0.281 g, 0.539 mmol) in DMF (5 mL) was treated with triethylamine (0.226 mL, 1.62 mmol). The reaction mixture was stirred at room temperature for 90 minutes and then diluted with ethyl acetate (30 mL), washed with saturated aqueous sodium bicarbonate (20 mL), brine (5 mL), dried (MgSO₄), filtered and concentrated to dryness. The residue was triturated with 5:1 ether/dichloromethane. Solids were collected by filtration and product was purified on a short path of silica gel using 50% ethyl acetate/DCM followed by 5% methanol/DCM to provide benzyl 6-(4-methoxyphenylsulfamoyl)-5S-{4-methyl-2S-[4-(2-pyridin-3-ylaminothiazol-4-yl)benzoylamino]-pentanoylamino}hexylcarbamate. R_(f) (TLC: 10% methanol/DCM): 0.45. ¹H NMR (DMSO-d⁶): 0.88 (6H, 2×d); 0.9-1.75 (9H, m*); 2.93 (2H, m); 3.09 (2H, m); 3.69 (3H, s); 4.19 (1H, m); 4.39 (1H, m); 4.99 (2H, s). 6.88 (2H, m); 7.13-7.7.45 (9H, m); 7.57 (1H, s); 7.98 (5H, m*); 8.19 (1H, d, J=5 Hz); 8.29 (1H, d, J=7 Hz); 8.43 (1H, d, J=6 Hz); 8.86 (1H, d, J=2.4 Hz); 9.45 (1H, s); 10.6 (1H, s). MS (M+1): 8.28.

[0246] Proceeding as in Example 3 the following compounds of Formula I were prepared:

[0247] N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methy-butyl}-4-(2-pyridin-3-ylaminothiazol-4-yl)benzamide (Compound 16); ¹H NMR (DMSO-d⁶) 0.87 (6H, 2×d); 1.23 (1H, m*); 1.5-1.86 (3H, m*); 1.99 (1H, m); 2.59 (2H, m); 3.15 (2H, m); 3.70 (3H, s); 4.24 (1H, m); 4.47 (1H, m); 6.87 (2H, d, J=9 Hz); 7.14-7.25 (7H, m); 7.43 (1H, dd); 7.58 (1H, s); 7.99 (4H, 2×d); 8.14 (1H, d); 8.19 (1H, d); 8.3 (1H, d); 8.53 (1H, d); 8.86 (1H, d); 9.48 (1H, s); 10.55 (1H, s). MS (M+1): 727.

Example 4 Synthesis of N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}nicotinamide

[0248]

[0249] A mixture comprised of 2S-amino-N-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropyl]-4-methylpentanamide hydrochloride (110 mg, 0.227 mmol), prepared as in Reference 6, and nicotinyl chloride hydrochloride (44 mg, 0.227 mmol) in THF (2 mL) and DCM (2 mL) was treated with triethylamine (0.095 mL, 0.682 mmol). The mixture was stirred at room temperature for 3 hours and then diluted with ethyl acetate (25 mL). The dilution was washed with saturated sodium bicarbonate(5 mL), dried (MgSO₄), filtered and concentrated to dryness. The residue was dissolved in DCM/diethyl ether/hexane and product was crystallized to provide N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}nicotinamide (63 mg, 50% yield). R_(f) (TLC, 50% ethyl acetate/DCM): 0.25. ¹H NMR (CDCl₃): 0.92-0.97 (6H, 2×d); 1.7-1.81 (4H, m*); 1.95 (1H, m); 2.54 (2H, m); 3.16 (2H, dd); 3.78 (3H, s); 4.30 (1H, m); 4.59 (1H, m); 6.74 (2H, d, J=9 Hz); 6.89 (1H, d, J=8 Hz); 7.02-7.24 (8H, m); 7.37 (1H, dd); 7.96 (1H, br s); 8.12 (1H, d, J=8 Hz); 8.71 (1H, br s); 9.06 (1H, br s). MS (M+1): 553.

[0250] Proceeding as in Example 4 provided:

[0251] N-{1S-[1S-(4-methoxyphenylsulfamoyl-methyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}-isonicotinamide (Compound 20); R_(f) (TLC, 20% ethyl acetate/DCM); 0.1; ¹H NMR (CDCl₃): 0.96 (6H, 2×d); 1.65-1.89 (4H, m*); 1.98 (1H, m); 2.57 (2H, m); 3.16 (2H, 2×dd); 3.75 (3H, s); 4.30 (1H, m); 4.59 (1H, m); 6.75 (3H, d, m*); 6.85 (1H, d, J=8 Hz); 7.05-7.24 (7H, m); 7.59 (3H, m); 8.71 (2H, d); MS (M+1): 553.

Example 5 Synthesis of N-{1-[1-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}-1H-indole-5-carboxamide

[0252]

[0253] A mixture comprised of and 2S-amino-N-[1S-(4-methoxyphenylsulfamoyl-methyl)-3-phenylpropyl]-4-methylpentanamide hydrochloride (0.100 g, 0.206 mmol), prepared as in Reference 6, and 5-indolecarboxylic acid (33.3 mg, 0.206 mmol) in DCM (2 mL) was treated with triethylamine (0.029 mL, 0.206 mmol) and DCC (0.206 mL of a 1.0 M DCM solution). The reaction mixture was stirred at room temperature overnight and then eluted directly through a silica gel column (0-50% ethyl acetate/CH₂Cl₂ gradient). Product was crystallized from DCM/diethyl ether/hexane to provide N-{1-[1-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}-1H-indole-5-carboxamide (58 mg, 48% yield). R_(f) (TLC, 20% ethyl acetate/CH₂Cl₂): 0.2; NMR (CDCl₃): 0.97-1.02 (6H, 2×d, J=6 Hz); 1.64-1.98 (5H, m*); 2.54 (2H, m); 3.02-3.19 (2H, 2×dd); 3.74 (3H, s); 4.27 (1H, m); 6.48 (1H, d, J=7 Hz); 6.61 (1H, s, t); 6.75 (2H, d, J=9 Hz); 6.94-7.27 (9H, m*); 7.41 (1H, d); 7.61 (1H, dd); 7.87 (1H, s); 8.10 (1H, s); 8.47 (1H, br s); MS (M+1): 591.

[0254] Proceeding as in Example 5 provided:

[0255] tert-Butyl 3-{1S-[1S-(4-methoxyphenyl-sulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methyl-butylcarbamoylphenyl}carbamate (Compound 22); R_(f) (TLC, 20% ethyl acetate/CH₂Cl₂): 0.35; ¹H NMR (CDCl₃): 0.93-0.99 (6H, 2×d, J=6 Hz); 1.50 (9H, s); 1.42-1.85 (4H, m*); 1.98 (1H, m); 2.58 (2H, m); 3.13 (2H, m); 3.75 (3H, s); 4.30 (1H. m); 4.60 (1H, m); 6.53 (1H, d, J=7 Hz); 6.73 (2H, d, J=9 Hz); 7.0-7.4 (11H, m*); 7.62 (1H, d, J=7,5 Hz); 7.72 (1H, s); 7.78 (1H, s); MS (M+1): 667.

Example 6 Synthesis of 3-amino-N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}benzamide

[0256]

[0257] A solution comprised of tert-butyl 3-{1S-[1S-(4-methoxyphenylsulfamoyl-methyl)-3-phenylpropylcarbamoyl]-3-methylbutylcarbamoyl}phenylcarbamate (20 mg, 30 μmol), prepared as in Example 6, in methylene chloride (2 mL) was treated with a 4M solution of hydrochloric acid in dioxane (1 mL) at room temperature for 16 hours and then diluted with diethyl ether (100 mL) to form a precipitate. The precipitate was collected by filtration, washed with ether and dried in vacuo to provide 3-amino-N-{1S-[1S-(4-methoxyphenyl-sulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}benzamide (14.3 mg, 79% yield). MS (M+1, free base): 567.

Example 7 Synthesis of N-{1S-[5-amino-1S-(4-methoxyphenylsulfamoylmethyl)pentylcarbamoyl]-3-methyl-butyl}-4-(2-pyridin-3-ylaminothiazol-4-yl)benzamide hydrobromide

[0258]

[0259] A solution of benzyl 6-(4-methoxyphenylsulfamoyl)-5S-{4-methyl-2S-[4-(2-pyridin-3-ylamino-thiazol-4-yl)benzoylamino]pentanoylamino}hexylcarbamate (0.1 g, 0.121 mmol), prepared as in Example 3, in DCM (3 mL) was treated with 30% (0.1 g, 0.3 mL) solution of hydrogen bromide in glacial acetic acid for 3 hours. The solution was diluted with methanol/ether to form a precipitate which was isolated to provide N-{1S-[5-amino-1S-(4-methoxyphenylsulfamoylmethyl)pentylcarbamoyl]-3-methylbutyl}-4-(2-pyridin-3-ylaminothiazol-4-yl)benzamide hydrobromide (90 mg, 0.1 mmol). ¹H NMR (DMSO-d⁶): 9.88 (6H, 2×d); 1.2-1.71 (9H, m); 2.72 (2H, m); 3.12 (2H, m); 3.71 (3H, s); 4.22 (1H, m); 4.43 (1H. m); 6.89 (2H, d, J=9 Hz); 7.14 (2H, d, J=9 Hz);.75 (3H, s, m*); 8.00-8.06 (7H, m); 8.53-8.66 (3H, d, d, m*); 9.47 (1H, s); 9.56 (1H, d, J=2 Hz); 11.55 (1H, s). MS (M+1, free base): 6.94.

Example 8 Synthesis of benzyl 1S-{1S-[3-(1-hydroxyethyl) phenylsulfamoylmethyl]-3-phenylpropylcarbamoyl}-3-methylbutyl-carbamate

[0260]

[0261] A solution comprised of benzyl 1S-[1S-(3-acetylphenylsulfamoylmethyl)-3-phenylpropyl-carbamoyl]-3-methylbutylcarbamate (85 mg, 0.143 mmol), prepared as in Example 1, in THF (5 mL) was treated with sodium borohydride (10 mg, 0.266 mmol). Water (0.5 mL) was added and the mixture was stirred for 30 minutes. Saturated aqueous sodium bicarbonate (5 mL) and ethyl acetate (25 mL) were added and the mixture was stirred for 15 minutes. The organic phase was separated, dried (MgSO₄), filtered and concentrated to dryness to provide benzyl 1S-{1S-[3-(1-hydroxyethyl)-phenylsulfamoylmethyl]-3-phenylpropyl-carbamoyl}-3-methylbutylcarbamate (70 mg, 82% yield). R_(f) (TLC, 20% ethyl acetate/CH₂Cl₂): 0.2-0.3 (2 spots, corresponding to diastereomers at the hydroxyethyl group). MS( M+1): 596.

Example 9 Cathepsin B Assay

[0262] Solutions of test compounds in varying concentrations were prepared in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising:N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5 mM). Human cathepsin B (0.025 pMoles in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-FR-AMC (20 nMoles in 25 μL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at (λ460 nm) for 5 minutes. Apparent inhibition constants (K_(i)) were calculated from the enzyme progress curves using standard mathematical models.

[0263] Compounds of the invention were tested by the above-described assay and observed to exhibit cathepsin B inhibitory activity.

Example 10 Cathepsin K Assay

[0264] Solutions of test compounds in varying concentrations were prepared in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin K (0.0906 pMoles in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (4 nMoles in 25 μL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at (λ460 nm) for 5 minutes. Apparent inhibition constants (K_(i)) were calculated from the enzyme progress curves using standard mathematical models.

[0265] Compounds of the invention were tested by the above-described assay and observed to exhibit cathepsin K inhibitory activity.

Example 11 Cathepsin L Assay

[0266] Solutions of test compounds in varying concentrations were prepared in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (1 nMoles in 25 μL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at (λ460 nm) for 5 minutes. Apparent inhibition constants (K_(i)) were calculated from the enzyme progress curves using standard mathematical models.

[0267] Compounds of the invention were tested by the above-described assay and observed to exhibit cathepsin L inhibitory activity.

Example 12 Cathepsin S Assay

[0268] Solutions of test compounds in varying concentrations were prepared in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM). Human cathepsin S (0.158 pMoles in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-Val-Val-Arg-AMC (9 nMoles in 25 μL of assay buffer) was added to the assay solutions and hydrolysis was followed spectrophotometrically at (λ460 nm) for 5 minutes. Apparent inhibition constants (K_(i)) were calculated from the enzyme progress curves using standard mathematical models.

[0269] Compounds of the invention were tested by the above-described assay and observed to exhibit cathepsin S inhibitory activity.

Example 13

[0270] Representative Pharmaceutical Formulations Containing a Compound of Formula I:

Oral Formulation

[0271] Compound of Formula I 10-100 mg Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL

Intravenous Formulation

[0272] Compound of Formula I 0.1-10 mg Dextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL

Tablet Formulation

[0273] Compound of Formula I  1% Microcrystalline Cellulose 73% Stearic Acid 25% Colloidal Silica  1%

[0274] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. 

We claim:
 1. A compound of Formula I:

in which: R¹and R² independently are —R⁸, —X²OR⁸, —X²SR⁸, —X²S(O)R⁸, —X²S(O)₂R⁸, —X²C(O)R⁸, —X²C(OR⁷)R⁷R⁸, —X²C(O)OR⁸, —X²NR⁷R⁸, —X²NR⁷C(O)OR⁸, —X²C(O)NR⁷R⁸, —X²S(O)₂NR⁷R⁸, —X²NR⁷C(O)NR⁷R⁸ or —X²NR⁷C(NR⁷)NR⁷R⁸, wherein X² is (C₁₋₆)alkylene, R⁷ is hydrogen or (C₁₋₆)alkyl; R⁸ is hydrogen, (C₁₋₆)alkyl, (C₃-1₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicyclo-aryl(C₀₋₃)alkyl; wherein within R⁸ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with halo, —R⁹, —X³OR⁹, —X³SR⁹, —X³S(O)R⁹, —X³S(O)₂R⁹, —X³C(O)R⁹, —X³C(OR⁹)R⁹, —X³C(O)OR⁹, —X³NR⁹R¹⁰, —X³NR⁹C(O)OR⁹, —X³C(O)NR⁹R¹⁰, —X³S(O)₂NR⁹R¹⁰, —X³NR⁹C(O)NR⁹R¹⁰ or —X³NR⁹C(NR⁹)NR⁹R¹⁰; wherein X³ is a bond or (C₁₋₆)alkylene, R⁹ is hydrogen or (C₁₋₆)alkyl and R¹⁰ is cycloalkyl; R³ is —R¹¹, —X³OR¹¹, —X³SR¹¹, —X³S(O)R¹¹, —X³S(O)₂R¹¹, —X³C(O)R¹¹, —X³C(O)OR¹¹, —X³NR¹¹R¹², —X³NR¹²C(O)OR¹¹, —X³C(O)NR¹¹R¹², —X³S(O)₂NR¹¹R¹², —X³NR¹²C(O)NR¹¹R¹² or —X³NR¹²C(NR¹²)NR¹¹R¹², wherein X³ is as described above, R¹¹ is hydrogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl-(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl and R¹² is hydrogen or (C₁₋₆)alkyl, wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R³ are optionally independently substituted with halo, nitro, cyano, (C₁₋₆)alkyl, halo-substituted(C₁₋₆)alkyl, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —C(O)NR⁷R⁷, —S(O)₂NR⁷R⁷, —X²NR⁷R⁷, —X²NR⁷C(O)OR⁷, —X²NR⁷C(O)NR⁷R⁷ or —X²NR⁷C(NR⁷NR⁷R⁷, wherein X² and R⁷ are as defined above; R⁴ is hydrogen or (C₁₋₆)alkyl; R⁵ is (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, or —X²S(O)R¹⁴ where X² is as defined above and R¹⁴ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl; (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl; or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form (C₃₋₇)cycloalkylene; R⁶ is hydrogen or —X⁴X⁵R¹³, wherein X is —C(O)—, X⁵ is a bond, —O— or —NR¹²—, wherein R¹² is as defined above, and R¹³ is (C₁₋₆)alkyl, —R¹⁴, —X³OR¹⁴, —X³SR¹⁴, —X³S(O)R¹⁴, —X³S(O)₂R¹⁴, —X³C(O)R¹⁴, —X³C(O)OR¹⁴, —X³NR¹⁴R¹⁵,  X³NR¹⁵C(O)OR¹⁴, —X³C(O)NR¹⁴R¹⁵, —X³S(O)₂NR¹⁴R¹⁵, —X³NR¹⁵C(O)NR¹⁴R¹⁵ or —X³NR¹⁵C(NR¹⁵)NR¹⁴R¹⁵, wherein X³ is as defined above; R¹⁴ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl; R¹⁵ is hydrogen or (C₁₋₆)alkyl; and within R¹⁴ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —OCF₃, —CF₃, —OH, halo, —R¹⁶, —X³OR¹⁶, —X³OR¹⁵, —X³C(O)R¹⁵, —X³SR¹⁶, —X³S(O)R¹⁶, —R¹⁵, —X ³S(O)₂R¹⁶, —X³C(O)OR¹⁵, —X³NR¹⁵R¹⁵, —X³NR¹⁵C(O)OR¹⁵, —X³C(O)NR¹⁵R¹⁶, —X³S(O)₂NR¹⁵R¹⁶, —X³NR¹⁵C(O)NR¹⁵R¹⁵ or —X³NR¹⁵C(NR¹⁵)NR¹⁵R¹⁶, wherein X³ and R¹⁵ are as defined above and R¹⁶ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl-C₀₋₃)alkyl and within R¹⁶ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —R¹⁵, —R¹⁷, —X³OR¹⁷, —X³SR¹⁷, —X³S(O)R¹⁷, —X³S(O)₂R¹⁷, —X³C(O)R¹⁷, —X³C(O)OR¹⁷, —X³NR¹⁵R¹⁷, —X³NR¹⁵R¹⁵, —X³NR¹⁵C(O)OR¹⁷, —X³C(O)NR¹⁵R¹⁷, —X³S(O)₂NR¹⁵R¹⁷, —X³NR¹⁵C(O)NR¹⁵R¹⁷ or —X³NR¹⁵C(NR¹⁵)NR¹⁵R¹⁷, wherein X³ and R¹⁵ are as defined above and R¹⁷ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl and within R¹⁷ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —R¹⁸, —X³OR¹⁸, —X³SR¹⁸, -X³S(O)R¹⁸, —X³S(O)₂R¹⁸, —X³C(O)R¹⁸, —X³C(O)OR¹⁸, —X³NR¹⁵R¹⁸, —X³NR¹⁵C(O)OR¹⁸, —X³C(O)NR¹⁵R¹⁸, —X³S(O)₂NR¹⁵R¹⁸, —X³NR¹⁵C(O)NR¹⁵R¹⁸ or —X³NR¹⁵C(NR¹⁵)NR¹⁵R¹⁸, wherein X³ and R¹⁵ are as defined above and R¹⁸ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl; with the proviso that only one (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl is present within R⁶, or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 in which: R² is hydrogen; R¹ is —R⁸, —X²OR⁸, —X²C(O)R⁸, —X²C(OR⁷)R⁷R⁸, —X²NR⁷R⁸ or —X²NR⁷C(O)OR⁸ wherein X²is (C₁₋₆)alkylene; R⁷is hydrogen or (C₁₋₆)alkyl; R⁸ is hydrogen, (C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl or hetero(C₅₋₁₃)aryl(C₀₋₃)alkyl; wherein within R⁸ said cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted with halo, —R⁹, —X³OR⁹, —X³C(O)R⁹, —X³C(OR⁹)R⁹, —X³NR⁹R¹⁰ or —X³NR⁹C(O)OR⁹; wherein X³ is a bond or (C₁₋₆)alkylene, R⁹ is hydrogen or (C₁₋₆)alkyl and R¹⁰ is cycloalkyl; R³is —R¹¹, —X³NR¹¹R¹²or —X³NR¹²C(O)OR¹¹where R¹¹ is hydrogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl-(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl; R⁴is hydrogen or (C₁₋₆)alkyl; R⁵ is (C₁₋₆)alkyl or (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl; or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form (C₃₋₇)cycloalkylene; R⁶ is hydrogen or —X⁴X⁵R¹³, wherein X⁴ is —C(O)—, X⁵ is a bond, —O— or —NR¹²—, wherein R¹² is as defined above, and R¹³ is (C₁₋₆)alkyl or —R¹⁴ wherein R¹⁴ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl, hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, (C₉₋₁₂)bicycloaryl(C₀₋₃)alkyl or hetero(C₈₋₁₂)bicycloaryl(C₀₋₃)alkyl; and within R¹⁴ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —OCF₃, —CF₃, —OH, halo, —R¹⁶, —X³OR¹⁶, —X³OR¹⁵, —X³C(O)R¹⁵, —R¹⁵, —X³C(O)R¹⁶, —X³C(O)OR¹⁵, —X³NR¹⁵R¹⁵, —X³NR¹⁵C(O)OR¹⁵, wherein X³ and R¹⁵ are as defined above and R¹⁶ is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl or hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl, and within R¹⁶ said cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted with —R¹⁵, —R¹⁷, —X³NR¹⁵R¹⁷, or —X³NR¹⁵R¹⁵ wherein X³ and R¹⁵ are as defined above and R¹⁷is (C₃₋₁₂)cycloalkyl(C₀₋₃)alkyl, hetero(C₅₋₁₂)cycloalkyl(C₀₋₃)alkyl, (C₆₋₁₂)aryl(C₀₋₃)alkyl or hetero(C₅₋₁₂)aryl(C₀₋₃)alkyl.
 3. The compound of claim 1 wherein R¹ is 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-hydroxyphenyl, 2-acetyl-phenyl, 2-(1-hydroxyethyl)-phenyl, 2-phenylaminoethyl, pyridin-4-ylphenyl, pyridin-3-yl-phenyl, pyridin-2-ylphenyl, 1H-imidazol-2-yl, piperidin-4-yl or 1-methyl-piperidin-4-yl; and R² is hydrogen.
 4. The compound of claim 3 in which R³ is hydrogen, phenethyl, 4-amino-butyl, butyl or 4-benzyloxycarbonylaminobutyl.
 5. The compound of claim 4 in which R⁵ is isobutyl, sec-butyl or cyclohexylmethyl; and R⁴ is hydrogen, or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form cyclohexyl.
 6. The compound of claim 5 in which R⁶ is selected from the group consisting of benzoyl, morpholin-4-ylcarbonyl, acetyl, furan-3-ylcarbonyl, 2-methoxybenzoyl, 3-methoxybenzoyl, naphthalen-2-ylcarbonyl, benzo[1,3]dioxol-5-ylcarbonyl, 3-pyridin-3-ylacryloyl, benzofuran-2-ylcarbonyl furan-2-ylcarbonyl, tert-butoxycarbonyl, biphenyl-4-carbonyl, quinolin-2-ylcarbonyl, quinolin-3-ylcarbonyl, 3-acetylbenzoyl, 4-phenoxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, pyridin-3-ylcarbonyl, 3-(tert-butoxycarbonylaminomethyl)benzoyl, 4-carbonylpiperazin-1-ylcarboxylic acid tert-butyl ester, 4-carbonylpiperazin-1-ylcarboxylic acid ethyl ester, 4-(furan-2-ylcarbonyl)piperazin-1-ylcarbonyl, pyridin-4-ylcarbonyl, 1-oxypyridin-4-ylcarbonyl, 1-oxypyridin-3-ylcarbonyl, thiophen-2-ylcarbonyl, thiophen-3-ylcarbonyl, 4-benzoylbenzoyl, 5-methylthiophen-2-ylcarbonyl, 3-chlorothiophen-2-ylcarbonyl, 3-bromothiophen-2-ylcarbonyl, 4-chlorobenzoyl, 3-flouro-4-methoxybenzoyl, 4-methoxy-benzoyl, 4-triflouromethoxybenzoyl, 3,4-diflourobenzoyl, 4-fluorobenzoyl, 3,4-dimethoxy-benzoyl, 3-methylbenzoyl, 4-bromobenzoyl, 4-triflouromethylbenzoyl, 3-benzoylbenzoyl, cyclopentanecarbonyl, benzo[b]thiophen-2-ylcarbonyl, 3-chlorobenzo[b]thiophen-2-ylcarbonyl, formamylmethyl ester, 4-methylpentanoyl, formamylisobutyl ester, formamylmonoallyl ester, formamylisopropyl ester, N,N-dimethylformamyl, N-isopropylformamyl, N-pyridin-4-yl-formamyl, N-pyridin-3-ylformamyl, 3-phenylacryloyl, 1H-indol-5-ylcarbonyl, pyridin-2-ylcarbonyl, pyrazin-2-ylcarbonyl, 3-hydroxypyridin-2-ylcarbonyl, 2-aminopyridin-3-ylcarbonyl, 2-hydroxypyridin-3-ylcarbonyl, 6-aminopyridin-3-ylcarbonyl, 6-hydroxypyridin-3-ylcarbonyl, pyridazin-4-ylcarbonyl, 3-phenoxybenzoyl, 1-oxo-1,3-dihydroisoindol-2-ylcarbonyl, 4-(4-methylpiperazin-1-yl)benzoyl, 4-morpholin-4-ylbenzoyl, 4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzoyl, 4-(2-dimethylaminothiazol-4-yl)benzoyl, quinolin-6-ylcarbonyl, 4-dimethylamino-benzoyl, 3-aminobenzoyl, 4-methylpiperazin-1-ylcarbonyl and benzylacetyl.
 7. The compound of claim 1 wherein: R¹ is 4-methoxyphenyl, 3-acetylphenyl, 3-(1-hydroxyethyl)-phenyl, 2-(phenylamino)ethyl or 4-hydroxyphenyl; R² is hydrogen; R³ is hydrogen, 2-phenethyl, 4-aminobutyl, or 4-benzyloxycarbonylaminobutyl; R⁴ is hydrogen; R⁵ is isobutyl, sec-butyl or cyclohexylmethyl; or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form cyclohexyl; and R⁶ is selected from the group consisting of acetyl, pyridin-3-ylcarbonyl, 3-(tert-butoxycarbonylamino)benzoyl, pyridin-4-ylcarbonyl, 1H-indol-5-ylcarbonyl, benzyloxycarbonyl, 3-aminobenzoyl, 4-methylpiperazin-1-ylcarbonyl, quinolin-6-ylcarbonyl, 4-[2-(pyridin-3-ylamino)thiazol-4-yl]benzoyl, 4-dimethylaminobenzoyl, morpholin-4-yl-carbonyl, 4-(2-dimethylaminothiazol-4-yl)benzoyl, tert-butoxycarbonyl, 4-(4-ethylpiperazin-1-yl)-benzoyl, and 4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzoyl.
 8. The compound of claim 1 in which R⁶ is selected from the group consisting of benzoyl, morpholin-4-ylcarbonyl, acetyl, furan-3-ylcarbonyl, 2-methoxybenzoyl, 3-methoxybenzoyl, naphthalen-2-ylcarbonyl, benzo[1,3]dioxol-5-ylcarbonyl, 3-pyridin-3-ylacryloyl, benzofuran-2-ylcarbonyl, furan-2-ylcarbonyl, tert-butoxycarbonyl, biphenyl-4-carbonyl, quinolin-2-ylcarbonyl, quinolin-3-ylcarbonyl, 3-acetylbenzoyl, 4-phenoxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, pyridin-3-ylcarbonyl, 3-(tert-butoxycarbonylaminomethyl)benzoyl, 4-carbonylpiperazin-1-ylcarboxylic acid tert-butyl ester, 4-carbonylpiperazin-1-ylcarboxylic acid ethyl ester, 4-(furan-2-ylcarbonyl)piperazin-1-ylcarbonyl, pyridin-4-ylcarbonyl, 1-oxypyridin-4-ylcarbonyl, 1-oxypyridin-3-ylcarbonyl, thiophen-2-ylcarbonyl, thiophen-3-ylcarbonyl, 4-benzoylbenzoyl, 5-methylthiophen-2-ylcarbonyl, 3-chlorothiophen-2-ylcarbonyl, 3-bromothiophen-2-ylcarbonyl, 4-chlorobenzoyl, 3-flouro-4-methoxybenzoyl, 4-methoxy-benzoyl, 4-triflouromethoxybenzoyl, 3,4-diflourobenzoyl, 4-fluorobenzoyl, 3,4-dimethoxy-benzoyl, 3-methylbenzoyl, 4-bromobenzoyl, 4-triflouromethylbenzoyl, 3-benzoylbenzoyl, cyclopentanecarbonyl, benzo[b]thiophen-2-ylcarbonyl, 3-chlorobenzo[b]thiophen-2-ylcarbonyl, formamylmethyl ester, 4-methylpentanoyl, formamylisobutyl ester, formamylmonoallyl ester, formamylisopropyl ester, N,N-dimethylformamyl, N-isopropylformamyl, N-pyridin-4-yl-formamyl, N-pyridin-3-ylformamyl, 3-phenylacryloyl, 1H-indol-5-ylcarbonyl, pyridin-2-ylcarbonyl, pyrazin-2-ylcarbonyl, 3-hydroxypyridin-2-ylcarbonyl, 2-aminopyridin-3-ylcarbonyl, 2-hydroxypyridin-3-ylcarbonyl, 6-aminopyridin-3-ylcarbonyl, 6-hydroxypyridin-3-ylcarbonyl, pyridazin-4-ylcarbonyl, 3-phenoxybenzoyl, 1-oxo-1,3-dihydroisoindol-2-ylcarbonyl, 4-(4-methylpiperazin-1-yl)benzoyl, 4-morpholin-4-ylbenzoyl, 4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzoyl, 3-aminobenzoyl, 4-methylpiperazin-1-ylcarbonyl and benzylacetyl.
 9. A compound selected from the group consisting of: benzyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-carbamate; benzyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-2-methyl-butyl)-carbamate; tert-butyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-carbamate; benzyl (1S-{1S-[(3-acetyl-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-carbamate; N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-2-methylbutyl}-4-methylpiperazine-1-carboxamide; benzyl {1S-[2-(4-methoxyphenylsulfamoyl)-ethylcarbamoyl]-2-methyl-butyl}-carbamate; (2-cyclohexyl-1S-{3-phenyl-1S-[(2-phenylaminoethylsulfamoyl)-methyl]-propylcarbamoyl}ethyl)-carbamic acid tert-butyl ester; 4-dimethylamino-N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methylbutyl)-benzamide; quinoline-6-carboxylic acid (1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-amide; morpholine-4-carboxylic acid (2-cyclohexyl-1S-{3-phenyl-1S-[(2-phenylamino-ethylsulfamoyl)methyl]-propylcarbamoyl}ethyl)amide; 4-(2-dimethylaminothiazol-4-yl)-N-{1SS-[2-(4-methoxyphenylsulfamoyl)-ethylcarbamoyl]-3-methyl-butyl}benzamide; 2S-acetylamino-3-cyclohexyl-N-{1-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propyl}propionamide; 2R-acetylamino-3-cyclohexyl-N-{1-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propyl}propionamide; 2RS-acetylamino-3-cyclohexyl-N-{1-[(4-hydroxyphenylsulfamoyl)methyl]-3-phenyl-propyl}-propionamide; benzyl [6-(4-methoxyphenylsulfamoyl)-5S-(4-methyl-2S-{4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzoylamino}pentanoylamino)hexyl]carbamate; N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenylpropylcarbamoyl}-3-methyl-butyl)-4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzamide; N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-nicotinamide; N-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-3-methyl-butyl)-isonicotinamide; N-{1-[1-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}-1H-indole-5-carboxamide; tert-butyl [3-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-3-methyl-butylcarbamoyl)phenyl]-carbamate; 3-amino-N-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-1-3-methyl-butyl)-benzamide; N-(1S-{5-amino-1S-[(4-methoxyphenylsulfamoyl)methyl]pentylcarbamoyl}-3-methyl-butyl)-4-[2-(pyridin-3-ylamino)-thiazol-4-yl]-benzamide; benzyl [1S-(1S-{[3-(1-hydroxyethyl)phenylsulfamoyl]methyl}-3-phenylpropyl-carbamoyl)-3-methylbutyl]-carbamate; morpholine 4-carboxylic acid (1S-{5-amino-1S-[(4-methoxyphenylsulfamoyl)methyl]-pentylcarbamoyl}-2-phenylmethanesulfonylethyl)amide; (5S-[2S-(morpholin-4-ylcarbonyl)amino]-3-phenylmethanesulfonylpropionylamino}-6-phenylsulfamoylhexyl)carbamic acid benzyl ester; morpholine 4-carboxylic acid (1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenylpropylcarbamoyl}2-phenylmethanesulfonylethyl)amide; N-(1S-{1S-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-cyclohexyl)-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide; and N-(1S-{1S-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-cyclohexyl)-4-(4-propylpiperazin-1-yl)-benzamide; or a pharmaceutically acceptable salt thereof.
 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable excipient(s).
 11. The composition of claim 10 which further comprises one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effective amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof.
 12. The composition of claim 11 wherein the bisphosphonic acid is selected from the group consisting of 1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid, 1-hydroxyethylidene-1,1-diphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid, 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof.
 13. The composition of claim 11 wherein the bisphosphonic acid is 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof.
 14. The composition of claim 11 which comprises 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.
 15. A method for treating a disease in an animal in which inhibition of a cysteine protease can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of claim 1 or a pharmaceutically acceptable salt thereof.
 16. The method of claim 15 wherein the disease is osteoporosis.
 17. The method of claim 16 wherein the animal is a human.
 18. The method of claim 17 wherein the human is a post-menopausal woman.
 19. The method of claim 18 wherein the cysteine protease activity is cathepsin K activity.
 20. A process for preparing a compound of claim 1 comprising: (A) reacting a compound of formula 4

where R¹, R², and R³ are as defined in claim 1 above; with a compound of formula 5:

where R⁶ is as defined in claim 1 above; or (B) reacting a compound of formula 7:

with an acid compound of formula R⁶OH or an acid derivative thereof, wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in claim 1 above; and (C) optionally converting a compound of Formula I into a pharmaceutically acceptable salt; (D) optionally converting a salt form of a compound of Formula I to non-salt form; (E) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide; (F) optionally converting an N-oxide form of a compound of Formula I its unoxidized form; (G) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers; (H) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; (I) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form; and (J) optionally modifying any of the R¹, R², R³,R⁴, R⁵ and R⁶ groups. 